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![Hereditary Ataxias
• Group1-
caused by enzymatic
defects,
autosomal recessive
manner and
typically present in
childhood; fortunately,
many of these are now
treatable
• Group 2-
progressive degenerative
ataxias
AR-Friedreich ataxia
autosomal dominant
spinocerebellar ataxias,
episodic
ataxias,dentatorubropallidol
uysian atrophy [DRPLA])
the very rare X-linked
ataxias.](https://image.slidesharecdn.com/ataxia-200605145854/85/Ataxia-32-320.jpg)
![• Laboratory Abnormalities in A-T
• Elevated and slowly increasing serum alpha-fetoprotein
levels after two years of age
• Low serum levels of immunoglobulins (IgA, IgG, IgG
subclasses, IgE) and lymphopenia (particularly affecting
T-lymphocytes)
• Spontaneous and X-ray induced chromosomal breaks
and rearrangements in cultured lymphocytes and
fibroblasts
• Reduced survival of cultured lymphocytes and
fibroblasts after exposure to ionizing radiation [209]
• Cerebellar atrophy detected by MRI](https://image.slidesharecdn.com/ataxia-200605145854/85/Ataxia-51-320.jpg)
More Related Content
Ataxia
- 1.
- 5. • ARCHICEREBELLUM/ FLOCCULO NODULAR/VESTIBULOCERELLUM • - Eye movements, gross balance and orientation • - Inferior cerebellar pudencle • PALLEOCEREBELLUM/ SPINOCEREBELLUM/ VERMIS & PAR VERMIAN REGION • - Posture, Muscle tone, Axial muscle • control, Locomotion • - Inferior/ middle/ superior pudencle • NEOCEREBELLUM/ CELEBELLAR HEMISPHERES/PONTO CEREBELLUM • - Coordinating movements, Fine motor control • - middle/ superior pudencle
- 6. Ataxia 1. Sensory Ataxia:results from the loss of sensory input from the lower extremities due to diseases of peripheral nerves, dorsal roots, dorsal columns of the spinal cord or medial lemnisci. 2. Cerebellar Ataxia: results from a lesion or degeneration focused in the body’s gait and balance center: the vermis of the cerebellum
- 7. Characteristic Sensory AtaxiaCerebellar Ataxia Location of lesion Peripheral nerve or posterior column disease Cerebellar vermis Gait Wide based gait High stepping gait Lurching, staggering On Exam Can look normal while sitting Loss of peripheral position and vibration sense +ve Romberg Unable to stay balanced sitting -worse if legs crossed, -worse with running / standing
- 8. Characteristic Sensory AtaxiaCerebellar Ataxia Associated Findings Loss of position and vibration sense extremities Intention tremor Scanning speech Hypotonia Ocular and limb dysmetria Speech Normal Often slurred Hints Patient often looks to feet to know their position in space Patient looks like acute alcohol intoxication
- 9. Approach to childwith ataxia
- 10. Approach to childwith ataxia • HISTORY Ensure that your patient is stable and comfortable and then proceed further. In addition to a thorough history, include the following pertinent questions: • 1. HPI: timing, onset, progression (congenital vs insidious vs acute), nature of ataxia, associated symptoms: fever, nausea, vomiting, lethargy, headache, head tilting? • a. Any previous episodes of ataxia? • b. Onset: any recent viral infection or cough? • c. Any medications, drugs or poisons possibly ingested? • d. Any alcohol or other illegal drugs? • e. Any trauma? • f. Is there the possibility of a suicide attempt? • g. Any change in mental status?
- 11. • 2. PMH: BirthHx: exposures , TORCHES (congenital infections including toxoplasmosis, rubella, CMV, Herpes, Syphillis), congenital anomalies (ataxia can be congenital or hereditary, but not appear until later). • 3. Family History: sickle cell, metabolic disease, epilepsy, migraines or Friedrich’s ataxia
- 12. • PHYSICAL EXAM •full physical exam including vital signs and growth parameters. • General: awake, alert, acute distress, dysmorphic features • Skin: scars, crusted varicella lesions • fluid in middle ear, cervical adenopathy, papilledema, hemorrhages • Chest: chest rales, arrhythmias, murmurs • Abdomen: hepatosplenomagaly, masses • MSK: decreased strength
- 14. • Neuro: fullneuro exam: cranial nerves, tone, power, reflexes, sensation (pain, vibration, light touch, temperature and proprioception),focal neurological findings Assessment of Ataxia (Testing Cerebellar Function): • truncal control. • ask the child to walk several steps with natural gait, then assess tandem gait (walk heel toe). ask the child to walk several times around an object (ie. chair). fall or lean towards the side of the lesion. • tremor • dysmetria • dysdiadochokinesia
- 15. • PROCEDURES FORINVESTIGATION • 1. Bloodwork: CBC and differential (infection) Electrolytes with bicarbonate (imbalances), Monospot Toxicology screen (for anticonvulsants, hypnotics and phenothiazines, for alcohol and drugs of abuse; for heavy metals) Consider metabolic screen and IgA (for ataxia telangiectasia) • 2. Urine: toxicology screen • 3. Lumbar Puncture: if differential includes meningitis and fundi are normal ; look for CSF protein if demyelinating disease is suspected. • 4. Imaging: Consider CT/ MRI if there are focal neurological findings. • 5. Consults: Neurology.
- 16. Cerebellar Dysfunction • Cerebellarlesions or dysfunction disturb regulation of muscle tone, motor control, and coordination of movement. • Hypotonia - typically seen with acute hemispheric lesions with hyporeflexia. usually a transient phenomenon after an acute lesion but can be seen in chronic lesions as well
- 17. • Ataxia isa broad term that refers to a disturbance in the smooth performance of voluntary motor acts. • abasia(inability to walk due to spasticity, chorea, or tremor), • asynergia (lack of coordination between parts that normally act in unison), • dysmetria(inaccuracy in judging distance or scale, resulting in undershoot or overshoot of intended position of limb or eye), .
- 18. • dysdiadochokinesia • impairedcheck/excessive rebound responses. • Cerebellar dysarthria produces abnormalities in articulation (slurring and inaccuracy in range, force and timing; patients sound as if inebriated) • phonation (vocal quality can be harsh or uneven), • resonation (a nasal quality is common), • prosody (patients tend to place equal and excessive emphasis on each syllable)
- 19. • Intention tremor. • Postural tremor is a rare manifestation • Eye movement abnormalities -pathologic nystagmus (smooth pursuit in one direction alternating with saccadic pursuit in the other). • Ocular dysmetria (conjugate overshoot or undershoot of a visual target accompanied by voluntary saccades)
- 20. • Nonmotor manifestationslike cerebellar cognitive affective syndrome has been described in patients with isolated cerebellar lesions of various etiologies, which can all produce alterations in executive functions, spatial cognition, personality, and language use.
- 21. Nonhereditary Causes ofAtaxia The most prevalent causes of acute cerebellar ataxia are viruses (e.g., coxsackievirus, rubeola, varicella), traumatic insults, and toxins (e.g., alcohol, barbiturates, antiepileptic drugs).
- 22. Selected Causes ofAtaxia in Childhood • Congenital • Agenesis of vermis of the cerebellum • Aplasia or dysplasia of the cerebellum • Basilar impression • Chiari malformation • Cerebellar dysplasia with microgyria, macrogyria, or agyria
- 23. Congenital • Cervical spinalbifida with herniation of the cerebellum (Chiari malformation, type 3) • Dandy-Walker syndrome • Encephalocele • Hydrocephalus (progressive) • Hypoplasia of the cerebellum
- 24. Degenerative and/or Genetic •Acute intermittent cerebellar ataxia • Ataxia, retinitis pigmentosa, deafness, vestibular abnormality, and intellectual deterioration • Ataxia-telangiectasia • Biemond posterior column ataxia • Cerebellar ataxia with deafness, anosmia, absent caloric responses, nonreactive pupils, and hyporeflexia • Cockayne syndrome • Dentate cerebellar ataxia (dyssynergia cerebellaris progressiva) • Familial ataxia with macular degeneration • Friedreich ataxia • Hereditary cerebellar ataxia, intellectual retardation, choreoathetosis, and eunuchoidism • Hereditary cerebellar ataxia with myotonia and cataracts
- 25. Degenerative and/or Genetic •Hypertrophic interstitial neuritis • Marie’s ataxia • Marinesco-Sjögren syndrome • Pelizaeus-Merzbacher disease • Periodic attacks of vertigo, diplopia, and ataxia—autosomal dominant inheritance • Posterior and lateral column difficulties, nystagmus, and muscle atrophy • Progressive cerebellar ataxia and epilepsy • Ramsay Hunt syndrome (myoclonic seizures and ataxia) • Roussy-Lévy syndrome • Spinocerebellar ataxia (SCAs); olivopontocerebellar ataxias
- 26. • Endocrinologic • Cretinism •Hypothyroidism • Infectious or Postinfectious • Acute cerebellar ataxia • Acute disseminated encephalomyelitis • Cerebellar abscess • Coxsackievirus,Diphtheria,Echovirus,Infectious mononucleosis (Epstein- Barr virus infection) • Infectious polyneuropathy,Japanese B encephalitis,Mumps encephalitis,Mycoplasma pneumoniae,Pertussis,Polio,Postbacterial meningitis,Rubeola,Tuberculosis,Typhoid,Varicella
- 27. • Metabolic • Abetalipoproteinemia •Argininosuccinic aciduria • Ataxia with vitamin E deficiency (AVED) • GM2 gangliosidosis (late) • Hartnup disease • Hyperalaninemia • Hyperammonemia I and II • Hypoglycemia • Kearns-Sayre syndrome • Leigh disease • Maple syrup urine disease (intermittent)
- 28. Metabolic • MERRF (Myoclonicepilepsy with ragged red fibers) • Metachromatic leukodystrophy • Mitochondrial complex defects (I, III, IV) • Multiple carboxylase deficiency (biotinidase deficiency) • Neuronal ceroid-lipofuscinosis • Neuropathy, ataxia, retinitis pigmentosa (NARP) • Niemann-Pick disease (late infantile) • 5-Oxoprolinuria • Pyruvate decarboxylase deficiency • Refsum disease • Sialidosis • Triose-phosphate isomerase deficiency • Tryptophanuria • Wernicke encephalopathy (thiamine or B1 deficiency
- 29. • Neoplastic • Frontallobe tumors • Hemispheric cerebellar tumors • Midline cerebellar tumors • Neuroblastoma • Pontine tumors (primarily gliomas) • Spinal cord tumors • Primary Psychogenic • Conversion reaction
- 30. • Toxic • Alcohol •Benzodiazepines • Carbamazepine • Clonazepam • Lead encephalopathy • Phenobarbital • Phenytoin • Primidone • Tick paralysis poisoning
- 31. • Traumatic • Acutecerebellar edema • Acute frontal lobe edema • Vascular • Angioblastoma of cerebellum • Basilar migraine • Cerebellar embolism • Cerebellar hemorrhage • Cerebellar thrombosis • Posterior cerebellar artery disease • Vasculitis • von Hippel-Lindau disease
- 32. Hereditary Ataxias • Group1- causedby enzymatic defects, autosomal recessive manner and typically present in childhood; fortunately, many of these are now treatable • Group 2- progressive degenerative ataxias AR-Friedreich ataxia autosomal dominant spinocerebellar ataxias, episodic ataxias,dentatorubropallidol uysian atrophy [DRPLA]) the very rare X-linked ataxias.
- 33. Treatable Causes ofInherited Ataxia Disorder Metabolic Abnormality Distinguishing ClinicalFeatures Treatment Ataxia with vitamin E deficiency Mutation in alpha- tocopherol transfer protein Ataxia, areflexia, retinopathy Vitamin E Bassen- Kornzweig syndrome Abetalipoproteinemia Acanthocytosis, retinitis pigmentosa, fat malabsorption Vitamin E Hartnup disease Tryptophan malabsorption Pellagra rash, intermittent ataxia Niacin Familial episodic ataxia type 1 and type 2 Mutations in potassium channel (KCNA1) and a1Avoltage-gated calcium channel, respectively Episodic attacks, worse with pregnancy or birth control pills Acetazolamid e
- 34. Mitochondrial complex defects Complexes I,III, IV Encephalomyelopat hy Possibly riboflavin, CoQ10, dichloroacetate Multiple carboxylase deficiency Biotinidase deficiency Alopecia, recurrent infections, variable organic aciduria Biotin Pyruvate dehydrogenase deficiency Block in E-M and Krebs cycle interface Lactic acidosis, ataxia Ketogenic diet, possibly dichloroacetate Refsum disease Phytanic acid, alpha-hydroxylase Retinitis pigmentosa, cardiomyopathy, hypertrophic neuropathy, ichthyosis Dietary restriction of phytanic acid Urea cycle defects Urea cycle enzymes Hyperammonemia Protein restriction, arginine, benzoate, alpha- ketoacids
- 35. Friedreich Ataxia • oneof the most common hereditary ataxias • Progressive gait ataxia around puberty wild, with a reeling or lurching quality
- 36. Friedreich Ataxia Clinical Manifestations •Bladder dysfunction (spastic bladder ) • upper extremities affected only late in the disease course. • typically require a wheelchair within fifteen years of symptom onset.
- 37. • facial weakness,with cerebellar dysarthria and dysphagia. • Lateral or horizontal nystagmus • Impairment of pupillary responsivity and limited extraocular movements ,cataracts, retinitis pigmentosa, and optic atrophy. • Auditory dysfunction • higher cortical function appears intact
- 38. Friedreich Ataxia • DTR(Lowerlimb ) lost • Late-onset disease can be spastic with hyperreflexia.. Cremasteric and abdominal reflexes may be lost. The masseter reflex remains intact • Virtually all facets of cerebellar function are involved, and both gross and fine coordination are affected. • Position sense, vibration sense,impaired. • Axonal sensory neuropathy • Hypertrophic cardiomyopathy is the leading cause of death in Friedreich ataxia patients.
- 39. • MRI studiesdocument atrophy of the upper cervical spinal cord and cerebellum. • Diagnosis is suggested by the clinical manifestations and sometimes by family history. The presence of an abnormal 5-hour glucose tolerance curve is corroborative. Spinal fluid findings may include elevated protein content and mild pleocytosis
- 41. • Friedreich ataxiais caused by an unstable GAA trinucleotide repeat in the first intron of X25, which decreases expression of the mitochondrial protein, frataxin
- 42. • Treatment • Idebenone,a short-chain analog of coenzyme Q10.16 at 5 or 10 mg/kg/day • Therapy with Vit E other antioxidants, iron chelators, and/or glutathione peroxidase mimetics has been suggested • interferon gamma (IFNγ) • Symptomatic treatment in the form of antispasticity agents can be helpful to relieve painful muscle spasms, and surgical correction of scoliosis is palliative.
- 43. Ataxia telangiectasia • Ataxiatelangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity.
- 44. • Mutation inDNA repair factor-ATM (Ataxia telangiectasia Mutated) • The neuropathological hallmark of A-T is diffuse degeneration or atrophy of the cerebellar vermis and hemispheres,
- 45. • Progressive cerebellarataxia • Oculomotar apraxia • Choreoathetosis • oculocutaneous telangiectasia • chronic sinupulmonary infections • Ataxia begins soon after child begins to walk
- 46. • Immunological manifestations -lowlevels of one or more classes of immunoglobulin(IgG, IgA, IgM or IgG subclasses), failure to make antibodies in response to vaccines or infections, and lymphopenia, especially affecting T-lymphocytes • Cancer -People with A-T have a highly increased incidence of cancers.(Lymphomas and leukemias) • Radiation sensitivity • Feeding, swallowing, and nutrition
- 47. • Poor growth •Insulin-resistant diabetes • early aging such as premature graying of the hair • Delayed pubertal development/gonadal dysgenesis • Acquired deformity of the feet ,Scoliosis
- 49. Classic Form MildForm Neurological Manifestations during the toddler years resulting in wheelchair dependency around the age of 10. - mild neurological deficits in childhood with slower age-related neurodegeneration. The predominant neurological symptoms or symptoms to present first may be myoclonus, dystonia,choreoathetosis or tremor with ataxia appearing later. Immunodeficiencie suffer from some type of immunodeficiency and/or lymphopenia Immunodeficiencies do occur, but are less common
- 50. Classic Form MildForm Pulmonary Disease Relatively common. Less common. Cancer Although malignancies in these individuals tend to occur at a younger age and are often lymphoid in nature, cancers in older individuals do occur and include both hematopoietic and non-hematopoietic malignancies Malignancies tend to appear later in life and include a higher proportion of non- hematopoietic cancers. The diagnosis of cancer can precede the diagnosis of A-T.
- 51. • Laboratory Abnormalitiesin A-T • Elevated and slowly increasing serum alpha-fetoprotein levels after two years of age • Low serum levels of immunoglobulins (IgA, IgG, IgG subclasses, IgE) and lymphopenia (particularly affecting T-lymphocytes) • Spontaneous and X-ray induced chromosomal breaks and rearrangements in cultured lymphocytes and fibroblasts • Reduced survival of cultured lymphocytes and fibroblasts after exposure to ionizing radiation [209] • Cerebellar atrophy detected by MRI
- 52. • Management • Themanagement and treatment of A-T is symptomatic and supportive • anti-Parkinson and anti-epileptic drugs may be useful in the management of symptoms • gamma globulin therapy and childhood immunizations • Chest physiotherapy and insufflator-exsufflator device
- 53. • gastrostomy tube(G-tube or feeding tube) • standard cancer treatment regimens need to be modified to avoid the use of radiation therapy and radiomimetic drugs • L-DOPA, anticholingeric drugs-improve basal ganglia • Loss of balance,impaired speech- amantadine,fluxetine • Tremors-gabapentin,clonazepam
- 54. Spinocerebellar Ataxia • Thedominantly inherited ataxias, now called spinocerebellar ataxias (SCAs), are progressive disorders in which the cerebellum slowly degenerates, often accompanied by degenerative changes in the brainstem and other parts of the central nervous system (and less commonly the peripheral nervous system)
- 55. • There arethree major genetic categories of SCAs : 1) expanded CAG/polyQ ataxias; 2) nonprotein coding repeat expansion ataxias; and 3) ataxias caused by conventional mutations (missense, deletion, insertion, duplication).
- 56. • A secondfeature of SCAs is the remarkably wide range in phenotype. This heterogeneity stems primarily from the fact that DNA repeat expansions, which cause the most common SCAs, can vary greatly in size. The tendency for expansions to change size is why these mutations are described as “dynamic.” • Larger expansions typically cause more severe, earlier- onset disease. • Smaller expansions cause later-onset disease with a more circumscribed pattern of degeneration.
- 57. SCA1 • SCA1 beginsas a gait disorder, evolving to severe four limb ataxia with dysarthria and leaving most patients wheelchair-bound within 15-20 years. • SCA1 is caused by polyQ-encoding CAG repeat expansions. • SCA1 manifest signs of widespread cerebellar and brainstem dysfunction with relatively little supratentorial involvement. • Neuropathologic findings include neuronal loss in the cerebellum and brainstem, and degeneration of spinocerebellar tracts.
- 58. SCA2 • characterized byataxia, dysarthria, slow saccades, and peripheral neuropathy. • Extremely slow saccades are very common but not pathognomonic. • The expanded CAG repeat in SCA2 encodes polyQ in the disease gene product, ataxin-2.
- 59. SCA3(Machado-Joseph Disease (MJD) •most often begins as a progressive ataxia accompanied by lid retraction and infrequent blinking (creating “staring eyes”), ophthalmoparesis, and impaired speech and swallowing. • Neuropathological findings include widespread degeneration of cerebellar afferent and efferent pathways, pontine and dentate nuclei,cell bodies of the substantia nigra, subthalamiC nucleus, globus pallidus, cranial motor nerve nuclei and anterior horns. • The mutation in SCA3 is an expanded CAG repeat that encodes polyQ in the disease gene product ataxin-3. • MJD varies widely depending on repeat length: early onset rigidity and dystonia for the largest expansions, adult onset ataxia for the medium sized expansions), and late-onset ataxia • The most variable feature of SCA3 is the degree of peripheral nervous system involvement
- 60. SCA5 • This rareand relatively pure form of slowly progressive dominant cerebellar ataxia is sometimes reported as the “Lincoln family ataxia”. • defective gene was recently discovered to be the SPTBN2 gene encoding ß-III spectrin
- 61. SCA6 • “milder” disease,most often manifesting as a “pure” cerebellar ataxia accompanied by dysarthria and gaze- evoked nystagmus. • decreased vibration and position sense, impaired upward gaze, and, late in the disease, spasticity and hyperreflexia. Eye movements are among the key findings in SCA6, ranging from difficulty fixating on moving objects to diplopia without marked ductional deficits. • The disease progresses more slowly than in other SCAs
- 62. • Episodic Ataxias •There are currently eight described episodic ataxias, all of which are rare dominant disorders characterized by intermittent ataxia. • EA1, EA2, and EA5 are caused by channelopathies; • EA6 is caused by mutation of a glutamate receptor; and • the causes of EA3, EA4, EA7, and EA8 are unknown.
- 63. Hereditary Spastic Ataxia •a heterogeneous group of disorders that combine the features of hereditary spastic paralysis and spinocerebellar ataxia. • present first with lower limb spasticity followed by ataxia, dysarthria, impaired ocular movements, and gait disturbance. • Autosomal dominant, recessive, and X-linked forms
- 64. Acute Ataxia • Acutecerebellar ataxia typically presents with rapidly progressive symptoms evolving over a few hours but at most over 1 to 2 days. • In cases associated with a prodromal illness, the onset of ataxia is usually within 1 to 3 weeks after the onset of the prodromal illness.
- 65. Causes of AcuteCerebellar Ataxia • Inflammatory • Infectious cerebellitis Postinfectious cerebellitis Brainstem encephalitis Acute disseminated encephalomyelitis Multiple sclerosis Vasculitis Paraneoplastic disorders Miller Fisher variant of Guillain–Barré syndrome • Intoxication Alcohol Drugs
- 66. • •Brain SpaceOccupying/Mass Lesions Tumors Abscesses Vascular Vertebrobasilar dissection Thromboembolism,CNS Trauma • Postconcussion syndrome Miscellaneous Labyrinthitis Basilar migraine Benign paroxysmal vertigo Epilepsy (nonconvulsive status, minor motor status)
- 67. Causes of AcuteEpisodic Cerebellar Ataxia Metabolic Disorders Genetic Disorders Mitochondrial disorders Urea cycle defects Aminoacidopathies Ataxia telangiectasia Episodic ataxias Organic acidopathies Spinocerebellar ataxias
- 68. Investigations in AcuteAtaxia • Computed Tomography and Magnetic Resonance Imaging • Cerebrospinal Fluid • Electromyography andElectroencephalography • Toxicology • Urinary Catecholamines/Metaiodobenzylguanidine Scintigraphy • Antibody levels
- 69. • Treatment andPrognosis • Acute postinfectious cerebellitis is usually a self-limited condition with most children showing a spontaneous recovery within the first week. After an active infection is ruled out, a trial of immunosuppression is usually warranted. Corticosteroids, such as solumedrol in a daily dose of 20 to 30 mg/kg up to 1000 mg a day, are usually pulsed for 3 to 5 days. If there is no improvement =plasmapheresis or intravenous immunoglobulin the use of rituximab 375 mg/m2 weekly for 4 weeks has been reported to show benefit
- 70. • OMAS frequentlyrequire prolonged treatment with IVIg and corticosteroids to prevent relapses. • Children with the Miller Fisher variant of GBS should be admitted to the hospital for careful monitoring of respiratory and autonomic function.. The recommended dose of immunoglobulin is 2 g/kg over 2 to 5 days. The decision for active treatment depends on status of ambulation and respiratory and bulbar involvement. • Systemic infections and brainstem encephalitis should be treated with standard antibiotic/antiviral protocols, although outcome in brainstem encephalitis is uncertain.
- 71. • Treatment oftoxic ingestion- no specific treatment is available. administration of an antidote, chelation, dialysis, • Ataxia related to postconcussion syndrome usually clears by 6 monthsataxia. • EA1 may respond to antiepileptic medication. Both EA1 and EA2 respond to daily acetazolamide. • Daily nicotinamide administration (50–300 mg) - neurologic complication in Hartnup disease. • Acetazolamide has been shown to abort acute attacks of ataxia in pyruvate dehydrogenase deficiency. • Nonmetastatic neuroblastoma should be removed surgically.