This document summarizes the clinical presentation and genetics of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. MELAS is caused by mutations in mitochondrial DNA and presents with a variety of neurological and systemic symptoms. The most common symptoms include stroke-like episodes, seizures, short stature, myopathy and lactic acidosis. Diagnosis is supported by finding ragged red fibers on muscle biopsy. Genetically, 80% of cases are caused by the m.3243A>G point mutation in the mitochondrial tRNALeu(UUR) gene. MELAS has highly variable clinical expression even within families and affected individuals may exhibit different combinations of symptoms.
CADASIL is caused by mutations in the NOTCH3 gene and is the most common monogenic form of cerebral small vessel disease. It is characterized clinically by recurrent strokes, cognitive decline, and mood disorders. Diagnosis involves identifying white matter changes, cerebral microbleeds, and NOTCH3 gene mutations on imaging and genetic testing. While there are currently no disease-modifying treatments, understanding the pathogenic mechanisms of CADASIL may help develop new therapeutic strategies.
This document provides an overview of peripheral neuropathy, including:
- Types of peripheral neuropathy are classified based on whether they primarily affect motor nerves, sensory nerves, or both.
- The main symptoms of motor, sensory, and autonomic neuropathies are described.
- The most common causes of peripheral neuropathy include systemic disorders like diabetes, connective tissue diseases, nutritional deficiencies, infections, malignancies and toxic neuropathies.
- The approach to evaluating a patient with peripheral neuropathy involves obtaining a history, neurological exam, electrodiagnostic studies and sometimes nerve biopsy to identify the location and cause of the neuropathy.
FA is a very rare, genetic, recessive disease, affecting 1/50,000 people.
Originates from mutations in the “coding” of the mitochondria.
Discovered by Nicholaus Friedreich in the early 1860’s.
Both parents must have the dominant trait for a 25% chance of an offspring possessing the disease.
Not necessarily a disease that kills you, but eventually a wheelchair and regular assistance will be required.
Onset before age 20-25 year.
This document provides an overview of white matter diseases. It discusses:
1. Primary demyelinating diseases like multiple sclerosis and neuromyelitis optica which are characterized by loss of myelin.
2. Secondary demyelination caused by known etiologies like infections, metabolic disorders, or vascular issues which result in destruction of both axons and myelin.
3. Dysmyelinating/hypomyelinating leukodystrophies which involve defective or incomplete myelin formation, including some common causes like metachromatic leukodystrophy.
4. The clinical approach involves considering features like onset, progression, family history, involvement of other organs, and patterns
Approach to a patient with bilateral vision lossNeurologyKota
This document discusses various causes of persistent bilateral visual loss in children and adults. In children, common non-progressive causes include congenital optic nerve anomalies such as optic nerve hypoplasia, morning glory disc anomaly, or optic nerve coloboma. In middle-aged or older adults, common causes of non-progressive bilateral visual loss include non-arteritic anterior ischemic optic neuropathy and glaucoma. Progressive bilateral visual loss can be caused by conditions affecting the optic nerves, chiasm, or retrochiasmal pathways such as pituitary tumors, aneurysms, or toxic/nutritional optic neuropathies. A thorough history, exam, and testing is needed to determine the underlying etiology in each case.
Hemiplegia is the total paralysis of one side of the body that can be caused by stroke, head trauma, brain tumors, or other neurological conditions. It is characterized by an inability to voluntarily move the arm, leg, and trunk on the same side of the body. Symptoms vary but can include difficulties with walking, balance, grasping objects, muscle stiffness, spasms, and speech or swallowing. Treatment involves rehabilitation to help regain motor function through exercises and may include pharmacological interventions or surgery depending on the underlying cause.
CADASIL is caused by mutations in the NOTCH3 gene and is the most common monogenic form of cerebral small vessel disease. It is characterized clinically by recurrent strokes, cognitive decline, and mood disorders. Diagnosis involves identifying white matter changes, cerebral microbleeds, and NOTCH3 gene mutations on imaging and genetic testing. While there are currently no disease-modifying treatments, understanding the pathogenic mechanisms of CADASIL may help develop new therapeutic strategies.
This document provides an overview of peripheral neuropathy, including:
- Types of peripheral neuropathy are classified based on whether they primarily affect motor nerves, sensory nerves, or both.
- The main symptoms of motor, sensory, and autonomic neuropathies are described.
- The most common causes of peripheral neuropathy include systemic disorders like diabetes, connective tissue diseases, nutritional deficiencies, infections, malignancies and toxic neuropathies.
- The approach to evaluating a patient with peripheral neuropathy involves obtaining a history, neurological exam, electrodiagnostic studies and sometimes nerve biopsy to identify the location and cause of the neuropathy.
FA is a very rare, genetic, recessive disease, affecting 1/50,000 people.
Originates from mutations in the “coding” of the mitochondria.
Discovered by Nicholaus Friedreich in the early 1860’s.
Both parents must have the dominant trait for a 25% chance of an offspring possessing the disease.
Not necessarily a disease that kills you, but eventually a wheelchair and regular assistance will be required.
Onset before age 20-25 year.
This document provides an overview of white matter diseases. It discusses:
1. Primary demyelinating diseases like multiple sclerosis and neuromyelitis optica which are characterized by loss of myelin.
2. Secondary demyelination caused by known etiologies like infections, metabolic disorders, or vascular issues which result in destruction of both axons and myelin.
3. Dysmyelinating/hypomyelinating leukodystrophies which involve defective or incomplete myelin formation, including some common causes like metachromatic leukodystrophy.
4. The clinical approach involves considering features like onset, progression, family history, involvement of other organs, and patterns
Approach to a patient with bilateral vision lossNeurologyKota
This document discusses various causes of persistent bilateral visual loss in children and adults. In children, common non-progressive causes include congenital optic nerve anomalies such as optic nerve hypoplasia, morning glory disc anomaly, or optic nerve coloboma. In middle-aged or older adults, common causes of non-progressive bilateral visual loss include non-arteritic anterior ischemic optic neuropathy and glaucoma. Progressive bilateral visual loss can be caused by conditions affecting the optic nerves, chiasm, or retrochiasmal pathways such as pituitary tumors, aneurysms, or toxic/nutritional optic neuropathies. A thorough history, exam, and testing is needed to determine the underlying etiology in each case.
Hemiplegia is the total paralysis of one side of the body that can be caused by stroke, head trauma, brain tumors, or other neurological conditions. It is characterized by an inability to voluntarily move the arm, leg, and trunk on the same side of the body. Symptoms vary but can include difficulties with walking, balance, grasping objects, muscle stiffness, spasms, and speech or swallowing. Treatment involves rehabilitation to help regain motor function through exercises and may include pharmacological interventions or surgery depending on the underlying cause.
Neurological complications frequently affect patients with chronic kidney disease and are important causes of morbidity and mortality. Some of the main neurological complications discussed in the document include uremic encephalopathy, polyneuropathy, and restless legs syndrome. Uremic encephalopathy can cause symptoms ranging from mild tremors to reduced consciousness and is generally reversible with adequate dialysis. Polyneuropathy manifests as a symmetric peripheral neuropathy that can be improved but not cured by dialysis and B vitamin supplementation. Restless legs syndrome, which involves unpleasant leg sensations relieved by movement, is associated with iron deficiency and can be treated with iron replacement or dopaminergic drugs.
This document provides guidance on evaluating acute headaches. It outlines important risk factors that suggest serious underlying causes, including sudden severe headaches, new headaches accompanied by neurological deficits, and headaches in certain high-risk populations. Evaluation may involve imaging like CT or MRI to rule out conditions such as subarachnoid hemorrhage, tumors, infections, or vascular abnormalities. The document also discusses distinguishing primary headache types and evaluating at-risk features to identify secondary headache causes.
MRI SPECTRUM OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROMENirav Kadvani
This document discusses the MRI spectrum of Posterior Reversible Encephalopathy Syndrome (PRES). It presents 9 case studies demonstrating various brain lesions seen in PRES patients, including watershed area lesions, frontal lobe lesions, occipital lobe lesions, splenial lesions, basal ganglia lesions, and cerebellar lesions. The document also reviews the definition, etiology, MRI features, differentials, and typical patterns of PRES lesions. In summary, PRES can involve multiple areas of the brain beyond just the posterior regions, and MRI is useful for evaluating and diagnosing this potentially reversible condition associated with high blood pressure or other predisposing factors.
This document discusses childhood stroke, including:
- Childhood stroke differs from adult stroke in its causes, which include cardiac abnormalities, infections, genetic conditions, and hematologic disorders rather than atherosclerosis.
- Diagnosing childhood stroke is challenging due to its rarity and non-specific clinical presentations. Imaging and laboratory tests are used to determine the cause and guide treatment.
- Treatment depends on the underlying cause but may include thrombolysis, anticoagulation, surgery, or lifestyle changes. Recurrence risks vary based on identified risk factors. Outcomes range from full recovery to lasting deficits, though prognosis is generally better than in adult strokes.
This study investigated the ability of continuous EEG (cEEG) monitoring to predict seizures in patients with intracerebral hemorrhage (ICH). The study found that lateralized periodic discharges (LPDs) on cEEG were significantly associated with increased seizure occurrence. The majority of seizures occurred without clinical signs, indicating the value of cEEG monitoring. Location of hemorrhage, neurological exam, or hemorrhage size did not predict seizures. This validates the potential use of prophylactic anti-epileptic drugs in ICH patients with LPDs on cEEG to prevent seizures.
This document discusses various types of autoimmune encephalitis. It begins by providing clues that can suggest an autoimmune cause over infectious, including a subacute onset and fluctuating course. It then covers several specific autoimmune encephalitis subtypes defined by the neuronal surface antigens involved, such as anti-NMDA receptor and anti-LGI1 encephalitis. For each subtype, it discusses clinical features, investigations, and treatment approaches. The document aims to help clinicians differentiate between autoimmune and infectious causes of encephalitis.
This document summarizes several demyelinating diseases of the central and peripheral nervous systems. It describes multiple sclerosis as the most common inflammatory demyelinating disease, affecting the brain and spinal cord, with classifications based on disease course. It also discusses central pontine myelinolysis, transverse myelitis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy. For each, it provides details on characteristics, causes, clinical manifestations, diagnosis, and treatment.
Demyelinating and Degenerative Disorders of the CNSGhie Santos
This document summarizes various demyelinating and degenerative disorders of the central nervous system (CNS). It discusses diseases that involve preferential damage to myelin such as multiple sclerosis and various leukodystrophies including metachromatic leukodystrophy and Krabbe disease. It also covers degenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease that are characterized by selective neuronal loss in specific brain regions. The morphology, pathogenesis, clinical features of each disease are described.
Mid brain anatomy and vascular syndromesNeurologyKota
The document discusses midbrain syndromes caused by lesions in different areas of the midbrain. It describes the anatomy and vascular supply of the midbrain. It then explains several midbrain syndromes - Parinaud's syndrome causes limited upward gaze; Claude's syndrome results in ipsilateral oculomotor palsy and contralateral ataxia; Benedikt's syndrome includes oculomotor palsy, ataxia, and contralateral hemiparesis; Weber's syndrome involves CN III palsy, contralateral hemiparesis and lower facial weakness. Nothnagel's syndrome involves oculomotor palsy and ipsilateral ataxia. The midbrain contains the superior and inferior
The document discusses progressive myoclonus epilepsy (PME), which consists of myoclonic seizures, tonic-clonic seizures, and progressive neurological dysfunction like ataxia and dementia. The main causes of PME include Unverricht-Lundborg disease, myoclonic epilepsy with ragged-red fiber syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidoses. Lafora body disease is characterized by myoclonus, seizures, ataxia, dementia and inclusion bodies. It has autosomal recessive inheritance and death usually occurs within 10 years of onset. Management involves treatment of seizures and myoclonus with medications like
This document discusses remyelinating therapies for multiple sclerosis (MS). It begins by explaining how MS results in demyelination and how remyelination can restore neuronal function. Several potential remyelinating therapies currently in preclinical or clinical trials are described, including clobetasol, opicinumab, guanabenz, and olesoxime. Biomarkers for measuring remyelination like diffusion tensor imaging, magnetization transfer imaging, and positron emission tomography are also summarized. The document concludes that while challenges remain, promising remyelinating strategies exist to provide benefit throughout the entire course of MS.
This document outlines Paraneoplastic Neurological Disorder (PND), including its history, definition, pathophysiology, clinical features, diagnosis criteria, treatment, and recommendations. PND is a neurological dysfunction associated with but not directly caused by cancer. It can affect the central, peripheral, or autonomic nervous systems. Onconeural antibodies are present in 60-70% of cases and help diagnose PND. Common PNDs include limbic encephalitis, cerebellar degeneration, and opsoclonus-myoclonus. Treatment involves treating the underlying cancer, immunotherapy like steroids or IVIg, and symptom management. Patients with suspected PND should be regularly screened for cancer for
Presentation1.pptx, radiological imaging of dementia.Abdellah Nazeer
This document discusses radiological imaging findings in various types of dementia. It provides examples of MRI, FDG-PET, and amyloid PET scans showing characteristic patterns of atrophy and hypometabolism in conditions like Alzheimer's disease, frontotemporal dementia, Creutzfeldt-Jakob disease, and others. Medial temporal lobe atrophy on MRI is highlighted as an important tool for the diagnosis of Alzheimer's, and FDG-PET can help differentiate Alzheimer's from frontotemporal dementia based on patterns of hypometabolism. Magnetic resonance spectroscopy is also discussed as a tool for assessing metabolic changes in Alzheimer's patients.
This document discusses Posterior Reversible Encephalopathy Syndrome (PRES). It begins with the historical background of the condition. PRES is characterized by reversible subcortical vasogenic brain edema that presents with neurological symptoms like seizures, headaches, and visual disturbances. It is often associated with issues like hypertension, renal failure, cytotoxic drugs, and preeclampsia. Brain imaging typically shows edema in the parieto-occipital regions that is usually reversible. The pathophysiology involves endothelial injury from abrupt blood pressure changes that causes breakdown of the blood-brain barrier and brain edema. PRES has diverse clinical manifestations and comorbid conditions that can trigger it. Diagnosis involves clinical context and supportive brain imaging findings.
Demyelinating diseases of the central nervous systemNazanin Ayareh
This document discusses demyelinating diseases of the central nervous system, focusing on multiple sclerosis. It describes the typical relapsing-remitting clinical course of MS and symptoms like vision changes, weakness, and abnormal sensations. Imaging plays an important role in diagnosis, and treatments include steroids for acute flares and disease-modifying drugs for long-term management of relapsing-remitting MS. The document also covers related conditions like clinically isolated syndrome and radiologically isolated syndrome.
Stroke is an emergency condition caused by a blocked artery or burst blood vessel in the brain. It can lead to serious disability or death if brain cells are not quickly treated. The main types of stroke are ischemic, caused by a blockage, and hemorrhagic, caused by a burst blood vessel. Timely treatment is critical to minimize brain cell death and damage. Management involves stabilizing vital functions, rapidly diagnosing the type of stroke, and administering appropriate treatments such as clot-busting drugs to reduce disability. A multidisciplinary approach is needed for long-term care and rehabilitation.
Subarachnoid hemorrhage occurs when there is bleeding into the subarachnoid space surrounding the brain. It is usually caused by the rupture of an intracranial aneurysm. Risk factors include age, family history, smoking, and hypertension. Patients often present with a sudden and severe headache described as "the worst headache of my life". Diagnosis is typically made through CT scan or lumbar puncture. Treatment involves securing the aneurysm through clipping or coiling to prevent rebleeding, as well as managing complications such as cerebral vasospasm, seizures, and hydrocephalus.
This document provides an overview of various demyelinating diseases of the central nervous system. It begins by defining demyelinating diseases as those involving disruption of myelin, which forms an insulating sheath around axons. It then classifies and describes several specific diseases, including acute disseminated encephalomyelitis (ADEM), inflammatory demyelinating pseudotumor, multiple sclerosis (MS), neuromyelitis optica, central pontine myelinolysis, HIV encephalopathy, progressive multifocal leukoencephalopathy (PML), and others. For each disease, it discusses clinical features, magnetic resonance imaging (MRI) findings, differential diagnoses, and pathology where relevant.
The document discusses diseases of white matter, focusing on primary demyelinating disorders. It describes how oligodendrocytes form myelin around axons, allowing for faster signal conduction. Primary demyelination can be caused by dysmyelinating disorders like leukodystrophies due to metabolic defects, or myelinoclastic disorders from immune attack on myelin. Specific leukodystrophies discussed include Krabbe disease, metachromatic leukodystrophy, and adrenoleukodystrophy. Multiple sclerosis is provided as a major example of an immune-mediated myelinoclastic disorder.
Mitochondrial Medicine Society MitoAction Updates 4.1.16mitoaction
Areas of discussion include: Transplantation in Mito patients, Stroke protocol for MELAS, Standards of care for Mito patients, Centers of Excellence and the need for community involvement/input (v2 slides)
This document discusses MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes), a mitochondrial disease. MELAS is most commonly caused by the A3243G mutation and is maternally inherited. It is characterized by stroke-like episodes typically beginning in the teenage years, as well as other symptoms like diabetes, deafness, and cognitive impairment. Brain imaging during episodes shows cortical lesions. Muscle biopsies may reveal abnormal mitochondria clustering in blood vessels. There is currently no cure, but certain treatments can help manage symptoms.
Neurological complications frequently affect patients with chronic kidney disease and are important causes of morbidity and mortality. Some of the main neurological complications discussed in the document include uremic encephalopathy, polyneuropathy, and restless legs syndrome. Uremic encephalopathy can cause symptoms ranging from mild tremors to reduced consciousness and is generally reversible with adequate dialysis. Polyneuropathy manifests as a symmetric peripheral neuropathy that can be improved but not cured by dialysis and B vitamin supplementation. Restless legs syndrome, which involves unpleasant leg sensations relieved by movement, is associated with iron deficiency and can be treated with iron replacement or dopaminergic drugs.
This document provides guidance on evaluating acute headaches. It outlines important risk factors that suggest serious underlying causes, including sudden severe headaches, new headaches accompanied by neurological deficits, and headaches in certain high-risk populations. Evaluation may involve imaging like CT or MRI to rule out conditions such as subarachnoid hemorrhage, tumors, infections, or vascular abnormalities. The document also discusses distinguishing primary headache types and evaluating at-risk features to identify secondary headache causes.
MRI SPECTRUM OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROMENirav Kadvani
This document discusses the MRI spectrum of Posterior Reversible Encephalopathy Syndrome (PRES). It presents 9 case studies demonstrating various brain lesions seen in PRES patients, including watershed area lesions, frontal lobe lesions, occipital lobe lesions, splenial lesions, basal ganglia lesions, and cerebellar lesions. The document also reviews the definition, etiology, MRI features, differentials, and typical patterns of PRES lesions. In summary, PRES can involve multiple areas of the brain beyond just the posterior regions, and MRI is useful for evaluating and diagnosing this potentially reversible condition associated with high blood pressure or other predisposing factors.
This document discusses childhood stroke, including:
- Childhood stroke differs from adult stroke in its causes, which include cardiac abnormalities, infections, genetic conditions, and hematologic disorders rather than atherosclerosis.
- Diagnosing childhood stroke is challenging due to its rarity and non-specific clinical presentations. Imaging and laboratory tests are used to determine the cause and guide treatment.
- Treatment depends on the underlying cause but may include thrombolysis, anticoagulation, surgery, or lifestyle changes. Recurrence risks vary based on identified risk factors. Outcomes range from full recovery to lasting deficits, though prognosis is generally better than in adult strokes.
This study investigated the ability of continuous EEG (cEEG) monitoring to predict seizures in patients with intracerebral hemorrhage (ICH). The study found that lateralized periodic discharges (LPDs) on cEEG were significantly associated with increased seizure occurrence. The majority of seizures occurred without clinical signs, indicating the value of cEEG monitoring. Location of hemorrhage, neurological exam, or hemorrhage size did not predict seizures. This validates the potential use of prophylactic anti-epileptic drugs in ICH patients with LPDs on cEEG to prevent seizures.
This document discusses various types of autoimmune encephalitis. It begins by providing clues that can suggest an autoimmune cause over infectious, including a subacute onset and fluctuating course. It then covers several specific autoimmune encephalitis subtypes defined by the neuronal surface antigens involved, such as anti-NMDA receptor and anti-LGI1 encephalitis. For each subtype, it discusses clinical features, investigations, and treatment approaches. The document aims to help clinicians differentiate between autoimmune and infectious causes of encephalitis.
This document summarizes several demyelinating diseases of the central and peripheral nervous systems. It describes multiple sclerosis as the most common inflammatory demyelinating disease, affecting the brain and spinal cord, with classifications based on disease course. It also discusses central pontine myelinolysis, transverse myelitis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy. For each, it provides details on characteristics, causes, clinical manifestations, diagnosis, and treatment.
Demyelinating and Degenerative Disorders of the CNSGhie Santos
This document summarizes various demyelinating and degenerative disorders of the central nervous system (CNS). It discusses diseases that involve preferential damage to myelin such as multiple sclerosis and various leukodystrophies including metachromatic leukodystrophy and Krabbe disease. It also covers degenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease that are characterized by selective neuronal loss in specific brain regions. The morphology, pathogenesis, clinical features of each disease are described.
Mid brain anatomy and vascular syndromesNeurologyKota
The document discusses midbrain syndromes caused by lesions in different areas of the midbrain. It describes the anatomy and vascular supply of the midbrain. It then explains several midbrain syndromes - Parinaud's syndrome causes limited upward gaze; Claude's syndrome results in ipsilateral oculomotor palsy and contralateral ataxia; Benedikt's syndrome includes oculomotor palsy, ataxia, and contralateral hemiparesis; Weber's syndrome involves CN III palsy, contralateral hemiparesis and lower facial weakness. Nothnagel's syndrome involves oculomotor palsy and ipsilateral ataxia. The midbrain contains the superior and inferior
The document discusses progressive myoclonus epilepsy (PME), which consists of myoclonic seizures, tonic-clonic seizures, and progressive neurological dysfunction like ataxia and dementia. The main causes of PME include Unverricht-Lundborg disease, myoclonic epilepsy with ragged-red fiber syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidoses. Lafora body disease is characterized by myoclonus, seizures, ataxia, dementia and inclusion bodies. It has autosomal recessive inheritance and death usually occurs within 10 years of onset. Management involves treatment of seizures and myoclonus with medications like
This document discusses remyelinating therapies for multiple sclerosis (MS). It begins by explaining how MS results in demyelination and how remyelination can restore neuronal function. Several potential remyelinating therapies currently in preclinical or clinical trials are described, including clobetasol, opicinumab, guanabenz, and olesoxime. Biomarkers for measuring remyelination like diffusion tensor imaging, magnetization transfer imaging, and positron emission tomography are also summarized. The document concludes that while challenges remain, promising remyelinating strategies exist to provide benefit throughout the entire course of MS.
This document outlines Paraneoplastic Neurological Disorder (PND), including its history, definition, pathophysiology, clinical features, diagnosis criteria, treatment, and recommendations. PND is a neurological dysfunction associated with but not directly caused by cancer. It can affect the central, peripheral, or autonomic nervous systems. Onconeural antibodies are present in 60-70% of cases and help diagnose PND. Common PNDs include limbic encephalitis, cerebellar degeneration, and opsoclonus-myoclonus. Treatment involves treating the underlying cancer, immunotherapy like steroids or IVIg, and symptom management. Patients with suspected PND should be regularly screened for cancer for
Presentation1.pptx, radiological imaging of dementia.Abdellah Nazeer
This document discusses radiological imaging findings in various types of dementia. It provides examples of MRI, FDG-PET, and amyloid PET scans showing characteristic patterns of atrophy and hypometabolism in conditions like Alzheimer's disease, frontotemporal dementia, Creutzfeldt-Jakob disease, and others. Medial temporal lobe atrophy on MRI is highlighted as an important tool for the diagnosis of Alzheimer's, and FDG-PET can help differentiate Alzheimer's from frontotemporal dementia based on patterns of hypometabolism. Magnetic resonance spectroscopy is also discussed as a tool for assessing metabolic changes in Alzheimer's patients.
This document discusses Posterior Reversible Encephalopathy Syndrome (PRES). It begins with the historical background of the condition. PRES is characterized by reversible subcortical vasogenic brain edema that presents with neurological symptoms like seizures, headaches, and visual disturbances. It is often associated with issues like hypertension, renal failure, cytotoxic drugs, and preeclampsia. Brain imaging typically shows edema in the parieto-occipital regions that is usually reversible. The pathophysiology involves endothelial injury from abrupt blood pressure changes that causes breakdown of the blood-brain barrier and brain edema. PRES has diverse clinical manifestations and comorbid conditions that can trigger it. Diagnosis involves clinical context and supportive brain imaging findings.
Demyelinating diseases of the central nervous systemNazanin Ayareh
This document discusses demyelinating diseases of the central nervous system, focusing on multiple sclerosis. It describes the typical relapsing-remitting clinical course of MS and symptoms like vision changes, weakness, and abnormal sensations. Imaging plays an important role in diagnosis, and treatments include steroids for acute flares and disease-modifying drugs for long-term management of relapsing-remitting MS. The document also covers related conditions like clinically isolated syndrome and radiologically isolated syndrome.
Stroke is an emergency condition caused by a blocked artery or burst blood vessel in the brain. It can lead to serious disability or death if brain cells are not quickly treated. The main types of stroke are ischemic, caused by a blockage, and hemorrhagic, caused by a burst blood vessel. Timely treatment is critical to minimize brain cell death and damage. Management involves stabilizing vital functions, rapidly diagnosing the type of stroke, and administering appropriate treatments such as clot-busting drugs to reduce disability. A multidisciplinary approach is needed for long-term care and rehabilitation.
Subarachnoid hemorrhage occurs when there is bleeding into the subarachnoid space surrounding the brain. It is usually caused by the rupture of an intracranial aneurysm. Risk factors include age, family history, smoking, and hypertension. Patients often present with a sudden and severe headache described as "the worst headache of my life". Diagnosis is typically made through CT scan or lumbar puncture. Treatment involves securing the aneurysm through clipping or coiling to prevent rebleeding, as well as managing complications such as cerebral vasospasm, seizures, and hydrocephalus.
This document provides an overview of various demyelinating diseases of the central nervous system. It begins by defining demyelinating diseases as those involving disruption of myelin, which forms an insulating sheath around axons. It then classifies and describes several specific diseases, including acute disseminated encephalomyelitis (ADEM), inflammatory demyelinating pseudotumor, multiple sclerosis (MS), neuromyelitis optica, central pontine myelinolysis, HIV encephalopathy, progressive multifocal leukoencephalopathy (PML), and others. For each disease, it discusses clinical features, magnetic resonance imaging (MRI) findings, differential diagnoses, and pathology where relevant.
The document discusses diseases of white matter, focusing on primary demyelinating disorders. It describes how oligodendrocytes form myelin around axons, allowing for faster signal conduction. Primary demyelination can be caused by dysmyelinating disorders like leukodystrophies due to metabolic defects, or myelinoclastic disorders from immune attack on myelin. Specific leukodystrophies discussed include Krabbe disease, metachromatic leukodystrophy, and adrenoleukodystrophy. Multiple sclerosis is provided as a major example of an immune-mediated myelinoclastic disorder.
Mitochondrial Medicine Society MitoAction Updates 4.1.16mitoaction
Areas of discussion include: Transplantation in Mito patients, Stroke protocol for MELAS, Standards of care for Mito patients, Centers of Excellence and the need for community involvement/input (v2 slides)
This document discusses MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes), a mitochondrial disease. MELAS is most commonly caused by the A3243G mutation and is maternally inherited. It is characterized by stroke-like episodes typically beginning in the teenage years, as well as other symptoms like diabetes, deafness, and cognitive impairment. Brain imaging during episodes shows cortical lesions. Muscle biopsies may reveal abnormal mitochondria clustering in blood vessels. There is currently no cure, but certain treatments can help manage symptoms.
Este documento define la vasculitis y proporciona detalles sobre la granulomatosis de Wegener. La vasculitis se caracteriza por inflamación y daño de los vasos sanguíneos, lo que puede causar isquemia en los tejidos afectados. La granulomatosis de Wegener es una forma especial de vasculitis granulomatosa que afecta principalmente las vías respiratorias superiores e inferiores y los riñones, causando síntomas como dolor nasal, tos, hemorragia pulmonar y falla renal. El diagnóstico se bas
This document provides clinical guidelines for pneumococcal vaccination in older adults. It describes pneumococcal disease as a leading cause of vaccine-preventable illness and death in the US, especially dangerous for young children and adults aged 65 and older. It recommends vaccination with PPSV23 for adults aged 65 and older, as well as younger adults with certain medical conditions that increase risk. PPSV23 protects against the 23 serotypes known to cause the majority of invasive pneumococcal disease. While it is effective at preventing severe disease, it may not prevent all cases of pneumococcal pneumonia.
- Mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA) and can affect multiple organ systems. They are characterized by failure of mitochondria to produce sufficient energy for cells.
- mtDNA is inherited solely from mothers and can be heteroplasmic, containing both mutated and normal mtDNA. This explains varying severity between mothers and children.
- The patient described presented with encephalopathy, lactic acidosis, strokes and other multi-system involvement consistent with a mitochondrial disorder. Whole mitochondrial genome sequencing detected a mtDNA deletion of unknown extent/genes involved.
- When evaluating for possible mitochondrial disease, consider if a patient has an unexplained combination of features like lactic acidosis,
Pneumococcal disease is caused by Streptococcus pneumoniae and remains a serious global health problem. It can cause infections like pneumonia, bacteremia, and meningitis. There are over 90 known serotypes of S. pneumoniae. Pneumonia is the most common clinical syndrome and a leading cause of death. Pneumococcal disease disproportionately affects young children, older adults, and those with underlying medical conditions. Vaccines provide an important strategy for prevention.
This document discusses mitochondrial diseases including MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes) and MERRF (Myoclonic Epilepsy with Ragged Red Fibers). It notes that mitochondrial genes are only inherited from the mother. MELAS is described as the most common inherited mitochondrial disease, with symptoms including strokes, muscle issues, and dementia, typically presenting in early teens. It is caused by mutations in mitochondrial DNA, most commonly a point mutation, and results in excess lactic acid production. MERRF is also described as causing similar symptoms and being caused by a mitochondrial gene mutation affecting tRNA. Treatment options for both include supplements like Co
Diagnostic Testing for Mitochondrial Diseasemitoaction
Review traditional diagnostic pathways
Discuss newer testing that has become available in recent years
Review new approaches to attempt to shorten time to diagnosis and increase precision
Exercise and nutrition in Mitochondrial Diseasemitoaction
Mark Tarnopolsky, MD, PhD, FRCP,
Depts. of Pediatrics (Neuromuscular + Neurometabolic Disease) and Medicine (Cell Biology/Metabolism, Neurology and Rehabilitation), McMaster University, Hamilton, CANADA
This document provides an overview of coma, including its definition, causes, signs and symptoms, diagnosis, treatment, and management. Coma is defined as a state of deep unconsciousness where the brain's alerting and arousal functions are affected. Causes can include metabolic abnormalities, infections, structural brain injuries, seizures, or lack of oxygen/glucose to the brain. Diagnosis involves assessing responsiveness using the Glasgow Coma Scale, examining pupils, ordering imaging tests, and determining the underlying cause. Treatment focuses on stabilizing the patient, treating any reversible causes, providing supportive care, and preventing increased intracranial pressure.
Neurocognitive disorders includes : Delirium and Dementia.
This presentation focuses on causes, risk factors, management and how to prevent its complication
This document discusses neurodegenerative diseases and their treatment. It defines neurodegenerative diseases as conditions that primarily affect neurons in the brain, causing problems with movement or mental functioning as neurons are damaged and die. The causes include a buildup of toxic proteins and mitochondrial dysfunction, generally resulting in programmed cell death of neurons. Stroke is also discussed, defined as occurring when a blood vessel blockage or rupture in the brain causes part of the brain to be deprived of oxygen. The two main types of stroke and their symptoms are outlined.
MOGAD is an inflammatory demyelinating disease of the CNS associated with antibodies targeting myelin oligodendrocyte glycoprotein (MOG). It can present with optic neuritis, acute disseminated encephalomyelitis (ADEM)-like attacks, brainstem syndromes, cerebral cortical encephalitis, or myelitis. MRI often shows large or longitudinally extensive lesions of the optic nerve, brain, or spinal cord. Pathology demonstrates perivenous demyelination, MOG-dominant myelin loss, and predominant CD4+ T-cell inflammation. MOGAD has a more heterogeneous clinical and radiological presentation compared to other CNS demyelinating diseases like multiple s
This document discusses stroke mimics and chameleons. It begins by introducing stroke mimics, which account for 20-25% of suspected stroke cases. Common mimics include seizures, hypoglycemia, sepsis, migraines, and tumors. Functional disorders and delirium can also mimic strokes. The document then discusses stroke chameleons, which imitate other diseases due to their gradual onset or non-specific symptoms. Examples given include vertigo, monoparesis, and delirium. Several case studies are presented to illustrate specific mimics and chameleons. The document emphasizes the importance of thorough clinical assessment to distinguish strokes from mimicking conditions.
The document discusses degenerative diseases of the brain that can cause dementia or non-dementing disorders. It describes several major dementing degenerative diseases including Alzheimer's disease, dementia with Lewy bodies, and vascular dementias. Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles leading to hippocampal and temporal lobe atrophy. Vascular dementia is caused by multiple infarcts visible as lesions on MRI. Non-dementing disorders discussed include Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. The document provides an overview of imaging and diagnostic features of these common neurodegenerative conditions.
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1. Introduction 336
Clinical abnormalities 336
Genetics and pathogenesis 340
Treatment 341
52
Mitochondrial encephalomyelopathy, lactic acidosis
and stroke-like episodes (MELAS)
MAJOR PHENOTYPIC EXPRESSION
Mitochondrial myopathy, shortness of stature, stroke-like episodes, seizures, encephalopathy progressive to dementia,
migraine,diabetes mellitus,lactic acidemia,ragged red muscle fibers and mutations in the mitochondrial tRNA leucine gene.
INTRODUCTION
This syndrome was first defined as such by Pavlakis and
colleagues [1] in 1984, although patients have doubtless been
reported earlier. Among the mitochondrial myopathies this is
one of the more common [2].
The typical clinical presentation includes all of the features
that make up the name of the syndrome, but there is enor-
mous variability. Some affected individuals have only diabetes,
or only migraine. Others have only hearing loss, or hearing
loss and diabetes [3]. The disease is inherited in a maternal
pattern, and the gene is on the mitochondrial genome
(Figure 52.1). Most of the patients have had one of two point
mutations in the mitochondrial gene for the leucine (UUR)
tRNA (A3243G and T3271C) [4–7] (Figure 52.2).
CLINICAL ABNORMALITIES
There is a considerable variety of expression consistent with
the varying heteroplasmy of mitochondrial inheritance. The
typical picture is of normal development followed by a severe,
progressive encephalomyopathy. Onset may be myopathic
with exercise intolerance or weakness (Figure 52.3). Many
patients have shortness of stature, and this may be the first
manifestation of disease (Figure 52.4). One of our patients
had been treated unsuccessfully with human growth hor-
mone by a pediatric endocrinologist; this has also been
reported by others. In many patients the onset of symptoms
is with the first stroke-like episode, usually between 4 and
ND5
Q
MELAS 3243G, 3271C
LHON 3460A
LHON 14448C
LHON 14449A
LHON 11778A
NARP 8993G/C
MERRF 8344G
DEAF 1555G
CY
ND6
Cyt bT
F P
E
12s
16s
PH
PL
QL
OH
ND1
W
D K
G
R
ND2
A
N
COI
COII
COIII
ATP8
ATP6
ND3
ND4
L
S
H
ND4L
I
M
LUUR
SUCN
V
Com
m
on
54kbdeletion–KSS
Figure 52.1 The circular DNA of the human mitochondrial genome.
Shown are the sites of the genes for the mitochondrial genes, as well
as the sites for the most common mutations, including the A3243G
and T3271C mutations associated with MELAS syndrome.
2. Clinical abnormalities 337
15 years-of-age [1,4,8–14]. Less commonly, the onset of dis-
ease may be in infancy [8], often with delayed developmental
milestones or learning disability.
The myopathy may be present before the first stroke. At
one extreme is a floppy infant at 4 months-of-age [8]. More
commonly, there is exercise intolerance, easy fatigability or
frank weakness. Patients may have difficulty going up stairs.
Myopathy may be progressive. Proximal muscles tend to be
more involved than the distal [8]. Musculature is generally
thin.The facial appearance may be myopathic [15].The creatine
phosphokinase activity in the blood may be elevated [13,16].
Some patients have been diagnosed as having polymyositis [11].
The electromyogram (EMG) may demonstrate a myopathic
pattern.
The stroke-like episode is the hallmark feature of this syn-
drome. At the same time, these episodes may occur in only a
few members of a pedigree, in which a much larger number
has the same mutation [15,16]. In one series of four families
[16] stroke-like episodes occurred only in the probands. Two
of the affected mothers were clinically entirely normal. In
other pedigrees no member may have had this defining man-
ifestation. The episode may initially be manifest by vomiting
and headache, convulsions or visual abnormalities [8]. Less
commonly, there may be numbness, hemiplegia or aphasia.
There may be recurrent episodes of headache or vomiting
lasting a few hours to several days. The episode may be fol-
lowed by transient hemiplegia or hemianopia lasting a few
hours to several weeks. Computed tomography (CT) or mag-
netic resonance imaging (MRI) scan of the brain following
such an episode reveals lucency consistent with infarction [17]
A
T A
T A
T A
A T
A T
A T
A T
A T
A
A
A
AA
A
A
A A
A
A
A
A A
A
A T
T T
T
T
T
T
T
T
T
T
T
T
G
G
G G
G
G
G
G
G
G
G
G
G
G C
C
C
C
C
C
C
C
CC
C
C C
C
C
C
5Ј-G C
3Ј-OH
MELAS
np3243
Mitochondrial
encephalomyopathy
or MELAS
np3252
MELAS
np3271
Anticodon
Figure 52.2 The tRNA for leucine, the site of the defect in the
MELAS syndrome. In addition to the point mutation at npA3243G,
the common mutation in MELAS, and npT3271C and npA3252G the
other MELAS mutations, there are a number of other known mutations
in the tRNA leucine which cause mitochondrial diseases. These
include: npT3250C, mitochondrial myopathy; npA3751G chronic
progressive external ophthalmoplegia (CPEO) proximal weakness,
sudden death; npA3260G, adult onset hypertrophic cardiomyopathy
and myopathy; npA3302G, mitochondrial myopathy; and npC3303T,
adult onset hypertrophic cardiomyopathy and myopathy.
Figure 52.3 K.S., a boy with MELAS illustrating his lordotic,
myopathic posture. He presented at 4 years-of-age with weakness
and exercise intolerance. He also had insulin-dependent diabetes
mellitus. Blood concentration of CPK was 462IU/L. Plasma
lactate was 93.1mg/dL. (This illustration was kindly provided
by Dr. Richard Haas of UCSD.)
Figure 52.4 N.F., a boy with MELAS who had strokes on three
occasions and had become demented. Stature was very short.
(This illustration was kindly provided by Dr. Richard Haas of UCSD.)
3. (Figures 52.5 and 52.6). This picture may resolve over hours
or days, but later there may be cerebral atrophy and calcifica-
tions, especially in the basal ganglia [17–24] (Figure 52.6).
Infarcts are most common in the posterior temporal, pari-
etal or occipital lobes, but histologic examination may reveal
clear-cut infarcts widely scattered in the cerebrum, cerebel-
lum or basal ganglia [18,20,25,26]. So these episodes are in
fact strokes. The term ‘stroke-like’may be appropriate in that
no vascular changes of inflammation or atherosclerosis are
found in the brain. We have tended to refer to this type of
lesion as metabolic stroke in other diseases, such as propionic
acidemia (Chapter 2) or methylmalonic acidemia (Chapter 3).
In MELAS mitochondrial angiopathy is evident in contrast
enhancement in affected areas [21,27–29], and even in the skin
as purpuric lesions.
The migraine or migraine-like headaches seen in these
patients may reflect the same process. Headache may be hemi-
cranial. In pedigrees of patients with classic MELAS there are
many members whose only manifestation is migraine [8,15]
(Figure 52.7). Developmental delay, or learning disability [8]
or attention deficit disorder [15], is mainly found in patients
prior to the development of the first stroke. This was the his-
tory of the patient illustrated in Figure 52.4 who did not have
his first stroke until the age of 8, but had been in a special
education program for years. On the other hand, some
patients with considerable myopathy and/or other sympto-
matology may be intellectually normal (Figure 52.3). The
encephalopathy when it develops may be progressive to
dementia (Figure 52.4). The patient may be apathetic and
cachectic [18].
Additional neurologic features include ataxia, tremor, dysto-
nia, visual disturbances and cortical blindness. Some have had
myoclonus. Convulsive seizures may be focal or generalized
tonic-clonic, but may also be myoclonic [7]. The electroen-
cephalogram (EEG) is usually abnormal, and there are usu-
ally epileptiform spike discharges.
Some patients have had ophthalmoplegia or ptosis [11].
Others have had pigmentary degeneration of the retina [30]
like those with the neurodegeneration, ataxia and retinitis
pigmentosa (NARP) mutation (Chapter 54). Patients have
been referred to as having the Kearns-Shy syndrome [11].
Others have presented with the picture of Leigh syndrome
(Chapter 47), in which patients have recurrent attacks of
338 MELAS
Figure 52.5 CT of the brain of M.R., a boy with the A3243 G
mutation, illustrating the posterior infarct and the extensive
calcifications in the basal ganglia, including the caudate, putamen
and globus pallidus. (Illustration kindly provided by Dr. Richard Haas
of UCSD.)
A
B
Figure 52.6 MRI of the brain of N.F. illustrating widespread
cortical atrophy, residual at a right parieto-occipital infarct with
ventriculomegaly and increased T2 signal representing preinfarction
state in left temporoparieto-occipital cortex. (This illustration kindly
provided by Dr. Richard Haas of UCSD.)
4. Clinical abnormalities 339
neurologic regression, pyramidal and extrapyramidal signs,
brainstem abnormalities and leukodystrophy [31,32].
An interesting consequence of the MELAS mutation is
the occurrence of diabetes mellitus [30] (Figure 52.7). This
appears to be the most common manifestation of MELAS. It
is usually type II diabetes [33],but the boy shown in Figure 52.3
had insulin-dependent diabetes mellitus.
Sensorineural hearing loss is another common manifesta-
tion, and it may be seen in individuals with or without diabetes
and no other manifestations of disease [3]. It may also be seen
in patients with the classic syndrome. Deafness has been
reported in about 25 percent of patients [8]. The disease is a
major cause of aminoglycoside-induced hearing loss [34]. This
provides an argument for screening for the MELAS mutation
in patients with antibiotic-induced deafness, in order to test
affected relatives and avoid aminoglycosides in them.
Cardiomyopathy is a less common feature, but may be
found in about 10 percent of patients. It is usually hyper-
trophic cardiomyopathy, but it may be dilated [35]. Patients
with the MELAS mutations have been found to have MELAS
and cardiomyopathy, but others have had isolated cardio-
myopathy and no neurologic disease. There may be conduc-
tion abnormalities – for instance, Wolff-Parkinson-White
syndrome [18] – and often an abnormal electrocardiogram
[36]. Huge accumulation of mitochondria has been observed
in myocardial fibers [18].
Renal involvement may take the form of renal tubular aci-
dosis, and there may be a typical renal Fanconi syndrome
[37]. One patient developed a nephrotic syndrome and had
focal glomerulosclerosis [16]. A variety of other organs has
been involved in individual patients. One had pancreatitis
following valproate administration [15]. Others have had
peripheral neuropathy with or without rhabdomyolysis [38,39].
One had ischemic colitis [40]. Pigmentary abnormalities of
the skin have been reported [37].
The histologic signature of the MELAS syndrome is the
appearance of ragged red fibers in the muscle (Figure 52.8)
[1,12,13,36]. These are best seen in the trichrome stain. In
H and E there may be variation in fiber size and increase in con-
nective tissue. Staining with periodic acid Schiff (PAS), NADH
tetrazolium reductase or for succinic dehydrogenase may show
increased subsarcolemmal activity. Electron microscopy reveals
an increase in number and size of mitochondria (Figure 52.9),
some with paracrystalline inclusion bodies [13,36].
The lactic acidosis is an important feature of this disorder. It
does not usually lead to systemic acidosis, and it may even be
absent in patients with impressive involvement of the central
nervous system. The levels may be elevated in cerebrospinal
fluid (CSF) and normal in blood [32].The patient in Figure 52.4
had repeated determinations of lactate in the blood in the
normal 20mg/dL range; his CSF lactate was 56.3mg/dL. The
CSF concentration of protein may be mildly elevated.
75ϩ
68
8
3
33 38 43
14 13
12
41
7 mo
41
47
55
63
7660’s MI
d57
in 1977
80ϩ
I.
II.
III.
IV.
Developmental delayed
seizures
Parkinson’s
Depression
MELAS
Migraine
Diabetes
Figure 52.7 Pedigree of the family of
N.F. illustrating the occurrence of diabetes,
migraine, seizures and other problems.
Analysis of the blood revealed the
npA3243G mutation.
Figure 52.8 Ragged red fibers of the muscle of a patient with
MELAS. (Illustration kindly provided by Dr. Richard Haas of UCSD.)
5. GENETICS AND PATHOGENESIS
The MELAS syndrome is the result of mutation in mitochondr-
ial genes for tRNA [41].The most common is A-to-G transition
at position 3243 of the tRNALeu(UUR) [4,5] (Figure 52.1).
Approximately 80 percent of affected individuals have this
mutation in the dihydrouridine loop of the gene [8,16,42–44].
The other common mutation, occurring in about 8.5 percent
of individuals, is also in the tRNALeu(UUR) at 3271 in the
anticodon,where there is a T-to-C transversion [7].The G-to-A
transversion at 3252 of the same gene has been reported in
mitochondrial encephalopathy [45]. Another mutation in the
dihydrouridine loop at nucleotide 3250 is a T-to-C transition
[42].Another mutation in this gene is an A-to-T change at posi-
tion 3256 [46].A 5814G in the tRNACys gene was reported in a
patient with cardiomyopathy and myopathy [35].
A quite distinct mutation,an A-to-G transition at nucleotide
11084 in the ND4 gene for the subunit of Complex I of the res-
piratory chain, was reported by Letrit et al. [47] in a Caucasian
patient. This same mutation was later reported by Sakuta and
colleagues [48] in 10–14 percent of Japanese studied, both
patients with mitochondrial myopathy and normal controls,
suggesting that it might be a polymorphism. On the other
hand, this mutation was not found in 109 normal or patient
Caucasians nor in American blacks, nor in a considerable
number of patients with other mitochondrial diseases. So the
issue on this transition is unresolved. A large (10.5kg) dele-
tion was reported in a MELAS patient with a renal Fanconi
syndrome [37].
The common mutation creates a new site for Hae III lead-
ing to a 169bp fragment in controls after electrophoresis and
fragments of 97 and 72bp in patients with MELAS [43].
Sequencing (Figure 52.10) reveals the G in MELAS where
there is an A in control.Varying heteroplasmy among affected
individuals appears to reflect variable segregation in the
ovum. On the other hand, study of the proportion of mutant
DNA in various tissues obtained from a woman and her
two daughters revealed similar proportions in tissues derived
from ectodermal, endodermal and mesodermal germ layers,
indicating little mitotic segregation after early embryogenesis
[49]. The issue of heteroplasmy, which can vary from tis-
sue to tissue making detection difficult has been addressed
in MELAS A3243G by the design of peptide nucleic acids
which bond to the wild type mtDNA at 3243 preventing
PCR amplification and making the mutant the dominant
product [50].
Mutations in the tRNA for leucine might be expected to
have an important effect on translation and hence protein
synthesis in mitochondria. This has been demonstrated in
studies of cybrids [25] by fusing human cell lines lacking
mitochondrial DNA with exogenous mitochondria contain-
ing 0 to 100 percent of the common 3243 mutant DNA.
Cybrids containing more than 95 percent mutant DNA had
decreased rates of synthesis and steady state levels of mito-
chondrial proteins leading to respiratory chain deficiency.
Patients with the MELAS syndrome have been found to
have marked deficiency in the activity of complex I of the
respiratory chain [12]. In mitochondria from muscle,
rotenone-sensitive NADH-cytochrome reductase activity was
0–27 percent of control value, and immunochemical study
revealed a general decrease in complex I subunits. In a patient
with the T-to-C 3250 mutation, complex I activity in muscle
was six percent of control and that of complex IV was 47 per-
cent of control [51]. The productions of CO2 from labeled
pyruvate, malate and 2-oxoglutarate were all reduced [36]. In
a study of four patients with the 3243 mutation, the activity
of complexes I and IV were reduced in muscle and other
340 MELAS
Figure 52.9 Electronmicroscopy of the muscle of the mother of
K.S. She had diabetes, but no symptoms of myopathy. Illustrated are
many pleomorphic mitochondria, abnormal concentric lamellar cristae
and electron-dense bodies. There is also glycogen accumulation.
(Illustration kindly provided by Dr. Richard Haas of UCSD.)
Figure 52.10 Sequencing gel of the MELAS region of the leucine
TRNA of muscle. The npA3243G mutation in K.S.; BB was a normal
control. (Illustration kindly provided by Dr. Richard Haas of UCSD.)
6. References 341
tissues, but there was no correlation between the proportion
of mutant DNA in a tissue and the activity of the respiratory
chain complexes [44].
TREATMENT
A variety of supportive measures is helpful in this disorder, as
in other mitochondrial diseases. Riboflavin therapy has been
reported to be of benefit in a patient with complex I defi-
ciency and the T-to-C 3250 mutation [51]. A dose of 20mg
twice a day was employed in a 2-year-old patient with myopa-
thy who could not ascend stairs and was reluctant to walk.
Improvement in muscle strength occurred, and there was no
further deterioration over three years of observation.
Coenzyme Q has been helpful in a number of patients [14].
Some amelioration of muscle weakness has been observed, as
well as some decrease in plasma levels of lactate. CSF lactate
did not improve. Doses of 30–90mg per day were reported
[14]. In MELAS, doses as high as 300mg per day have been
stated to be required for optimal effects [13,14].
Experience with dichloroacetic acid (Chapter 47) is accu-
mulating; it is clear that levels of lactate are lowered in both
plasma and CSF. MELAS may be one of the disorders that
responds favorably to this agent.
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