About and Diagnosis

1. Hepatocerebral
Mitochondrial
DEFININGTHE PROBLEMTO
DIAGNOSINGTHE SOLUTION
DRMAISTRY
NEWCASTLE

2. .
• Also known as MPV17-related
hepatocerebral mitochondrial
DNA depletion syndrome is an
inherited condition in
an autosomal recessive pattern.
• Which means both copies of the
gene in each cell have mutations.
• The parents of an individual with
an autosomal recessive condition
each carry one copy of the
mutated gene, but they typically
do not show signs and symptoms
of the condition.
This is an inherited disorder
that can cause liver disease
and neurological problems
About
Hepatocerebral
Mitochondrial
page 2

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Prevalence/Frequency
MPV17-related Hepatocerebral Mitochondrial DNA depletion
syndrome is thought to be a rare condition.
Approximately 30 cases have been described in the scientific
literature, including seven families with Navajo
neurohepatopathy.
Within the Navajo Nation of the southwestern United States,
Navajo neurohepatopathy is estimated to occur in 1 in 1,600
newborns.

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Signs&Symptoms
The signs and symptoms of this condition begin in infancy and typically
include vomiting, diarrhoea, and an inability to grow or gain weight at the
expected rate (failure to thrive).
Many affected infants have a buildup of a chemical called lactic acid in the
body (lactic acidosis) and hypoglycemia.
Within the first weeks of life, infants develop liver disease that quickly
progresses to liver failure.
The liver is frequently enlarged (hepatomegaly) and liver cells often have a
reduced ability to release a digestive fluid called bile (cholestasis)

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GeneticChanges
As the condition name suggests, mutations in the MPV17 gene cause
MPV17-related hepatocerebral mitochondrial DNA depletion syndrome.
The protein produced from the MPV17gene is located in the inner membrane
of cell structures called mitochondria.
Mitochondria are involved in a wide variety of cellular activities, including
energy production, chemical signaling, and regulation of cell growth,
division, and death.
Mitochondria contain their own DNA, known as mitochondrial DNA
(mtDNA), which is essential for the normal function of these structures.

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GeneticChanges continued…
It is likely that the MPV17 protein is involved in the maintenance of
mtDNA. Having an adequate amount of mtDNA is essential for normal
energy production within cells
.
MPV17 gene mutations that cause MPV17-related hepatocerebral
mitochondrial DNA depletion syndrome lead to production of a protein with
impaired function.
One mutation causes all cases of Navajo neurohepatopathy and results in
the production of an unstable MPV17 protein that is quickly broken down.
A dysfunctional or absent MPV17 protein leads to problems with the
maintenance of mtDNA, which can cause a reduction in the amount of
mtDNA (known as mitochondrial DNAdepletion).

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GeneticChanges continued…
Mitochondrial DNA depletion impairs mitochondrial function in many of
the body's cells and tissues, particularly the brain, liver, and other
tissues that have high energy requirements.
Reduced mitochondrial function in the liver and brain lead to the liver failure
and neurological dysfunction associated with MPV17-related
hepatocerebral mitochondrial DNA depletion syndrome.
Researchers suggest that the less mtDNA that is available in cells, the
more severe the features of Navajo neurohepatopathy.

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ClinicalCharacteristics
MPV17-related mitochondrial DNA (mtDNA) maintenance defect
presents in the vast majority of affected individuals as an early-onset
encephalohepatopathic (hepatocerebral) disease that is typically
associated with mtDNA depletion, particularly in the liver.
Mutations in this gene have been associated with the hepatocerebral form
of mitochondrial DNA depletion syndrome (MDS), a mutation in this protein
leads to an mtDNA (mitochondrial DNA) copy number decrease.

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ClinicalCharacteristicscontinued…
A later-onset neuromyopathic disease characterized by myopathy and
neuropathy, and associated with multiple mtDNA deletions in muscle, has
also rarely been described. MPV17-related mtDNA maintenance defect,
encephalohepatopathic form is characterized by:
• Hepatic manifestations (liver dysfunction that typically progresses to
liver failure, cholestasis, hepatomegaly, and steatosis);
• Neurologic involvement (developmental delay, hypotonia, microcephaly,
and motor and sensory peripheral neuropathy);
• Gastrointestinal manifestations (gastrointestinal dysmotility, feeding
difficulties, and failure to thrive); and
• Metabolic derangements (lactic acidosis and hypoglycemia).

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ClinicalCharacteristicscontinued…
Less frequent manifestations include renal tubulopathy,
nephrocalcinosis, and hypoparathyroidism.
Progressive liver disease often leads to death in infancy or early
childhood. Hepatocellular carcinoma has been reported.

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ClinicalManifestationsofMPV17-Related
Encephalohepatopathy
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Clinical Manifestations Frequency
Hepatic
Liver dysfunction 1
(100%)
Liver failure 2
(91%)
Cholestasis (73%)
Hepatomegaly (63%)
Steatosis (51%)
Liver cirrhosis (21%)
Hepatocellular cancer 3
(3%)
Neurologic 4
Developmental delay 5 (82%)
Hypotonia (74%)
Microcephaly (23%)
Peripheral neuropathy 6 (19%)
Seizures (10%)
Dystonia (4%)
Ataxia (3%)

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ClinicalManifestationsofMPV17-Related
Encephalohepatopathy
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Clinical Manifestations Frequency
Abnormalities
on brain MRI
White matter 7 (38%)
Brain stem signal (8%)
Basal ganglia signal (8%)
Gastrointestinal
Failure to thrive 8 (90%)
Gastrointestinal dysmotility 9 (33%)
Feeding difficulties (31%)
Metabolic
Lactic acidosis 10 (79%)
Hypoglycemia 11 (60%)
Other
Renal tubulopathy (10%)
Nephrocalcinosis (8%)
Hypoparathyroidism (4%)
Retinopathy (8%)

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ClinicalCharacteristics

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Diagnosis/Testing
page 14
The diagnosis of MPV17-related mtDNA maintenance defect is
established in a proband by the identification of biallelic pathogenic
variants in MPV17 by molecular genetic testing.

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Diagnosis/Testingcontinued…
Initial Diagnosis in Individuals with MPV17-Related mtDNA Maintenance Defect
Organ System Evaluation Comment
Gastrointestinal (liver)
Liver function tests
Liver transaminases (ALT &
AST), GGT, albumin, total &
direct bilirubin, & coagulation
profile INR(PT & PTT)
Liver ultrasound
To assess liver size, liver
texture, & for the presence of
masses
Alpha fetoprotein level
To screen for hepatocellular
carcinoma
Hepatology / liver
transplantation consultations
Nutrition evaluation
Consultation
w/gastroenterologist
If dysmotility is suspected
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Diagnosis/Testingcontinued…
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Initial Diagnosis in Individuals with MPV17-Related mtDNA Maintenance Defect
Organ System Evaluation Comment
Neurologic
Consultation w/neurologist
Developmental evaluation
By developmental
pediatrician
Brain MRI
To establish the degree of
central nervous system
involvement; as a baseline for
monitoring progression of
neurologic disease
Nerve conduction velocity
To establish the degree of
peripheral nervous system
involvement; as a baseline for
monitoring progression of
neurologic disease
Electroencephalogram If seizures are suspected

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Diagnosis/Testingcontinued…
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Initial Diagnosis in Individuals with MPV17-Related mtDNA Maintenance Defect
Organ System Evaluation Comment
Metabolic
Plasma glucose & lactate
concentrations
To assess lactic acidosis &
hypoglycemia
Renal
Urinalysis & urine amino
acids
To assess for renal
tubulopathy
Ocular Ophthalmologic examination
To assess corneal sensation
& possible corneal
ulcers/scarring
Other
Consultation w/clinical
geneticist &/or genetic
counselor

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TreatmentofManifestations
Management should involve a multidisciplinary team including specialists
in hepatology, neurology, nutrition, clinical genetics, and child
development.
Ideally management is by a multidisciplinary team including specialists in
hepatology, neurology, nutrition, clinical genetics, and child
development. Nutritional support should be provided by a dietitian
experienced in managing children with liver diseases; prevention of
hypoglycemia requires frequent feeds and uncooked cornstarch (1-2
g/kg/dose). Although liver transplantation remains the only treatment
option for liver failure, it is controversial because of the multisystem
involvement in this disorder.

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TreatmentofManifestationscontinued…
Prevention of secondary complications: Prevent nutritional deficiencies
(e.g., of fat-soluble vitamins) by ensuring adequate intake.
Surveillance: Monitor:
• Liver function to assess progression of liver disease;
• Serum alpha fetoprotein (AFP) concentration and hepatic ultrasound examination for
evidence of hepatocellular carcinoma;
• Development, neurologic status, and nutritional status.

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AutosomalRecessive
Inheritance

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Genetic counseling is the
process of providing
individuals and families with
information on the nature,
inheritance, and implications
of genetic disorders to help
them make informed medical
and personal decisions
GeneticCounseling
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MPV17-related mtDNA maintenance
defect is inherited in an autosomal
recessive manner.
Each sibling of an affected individual
has a 25% chance of being affected, a
50% chance of being an
asymptomatic carrier, and a 25%
chance of being unaffected and not a
carrier.
Carrier testing for at-risk relatives and
prenatal testing for a pregnancy at
increased risk are possible if the
pathogenic variants in the family are
known.

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ThankYou
Presented by:
Shaista Ramesar
Email: Shaista.ramesar@gmail.com
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