Mitochondrial Disease- ABMG Case Examples

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A molecular genetics laboratory informs you that an infant boy that you have evaluated with probable mitochondrial disease has a single mtDNA deletion. Of the following choices, what is the most appropriate approach regarding genetic counseling:

A. The recurrence risk is negligible for single mtDNA deletions.
B. The potential presence of a duplication must be addressed first before the recurrence risk can be stated.
C. Autosomal recessive or dominant inheritance is present.
D. Any inheritance pattern is possible in mitochondrial disease in general, and in this case in particular.

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Terms in this set (50)

B. Correct.
If a duplication is present, the recurrence risk may be substantial and the mother should be tested for the presence of the duplication. If a duplication is absent, the recurrence risk is probably low, although prenatal diagnosis could be offered.

A molecular genetics laboratory informs you that an infant boy that you have evaluated with probable mitochondrial disease has multiple mtDNA deletions. Of the following choices, what is the most appropriate approach regarding genetic counseling:

A. The recurrence risk is negligible for mtDNA deletions.
B. The potential presence of a duplication must be addressed first before the recurrence risk can be stated.
C. Autosomal recessive or dominant inheritance is present
D. Any inheritance pattern is possible in mitochondrial disease in general, and in this case in particular.

C. Correct.
Multiple mtDNA deletions are usually autosomal recessive or dominant in inheritance as the primary mutations are in nuclear-encoded genes that are involved in mtDNA replication or nucleotide pool maintenance.

Which of the following diseases can present with lactic acidosis and neuromuscular disease:

A. Which of the following diseases can present with lactic acidosis and neuromuscular disease:
mtDNA mutations
B. Nuclear-encoded subunits of the electron transport chain
C. Pyruvate dehydrogenase complex deficiency
D. A and B above
E. All of the above

Correct- E.

mtDNA mutations, nuclear-encoded subunits of the electron transport chain, pyruvate dehydrogenase complex deficiency, and defects in many other genes/proteins can
result in lactic acidosis and neuromuscular disease, which is a
common phenotype for mitochondrial disease in general.

Which electron transport chain complex(es) do not contain any mtDNA-encoded subunits?

A. Complex 2
B. Complex 3
C. Complex 5
D. Complexes 2 and 3
E. Complexes 1 and 4

Correct= A.

Complexes 1, 3, 4 and 5 all are composed of both mtDNA and nuclear-encoded subunits

mtDNA depletion is inherited in which of the following manners:

A. Maternal
B. Autosomal recessive
C. Sporadic
D. A or B above
E. A or C above

Correct: B

mtDNA changes in depletion are secondary to mutations in nuclear-encoded genes, and are inherited in an autosomal recessive manner.

A newborn male presents with severe lactic acidosis and congenital malformations of the brain and kidneys. A
maternal half brother died of a very similar illness. Among the
following, which is the most likely diagnosis:

A. MELAS
B. Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency
C. Leigh disease
D. Fumarase deficiency (a Krebs cycle defect)
E. Pyruvate dehydrogenase complex (PDHC) deficiency

Correct: E.

Most cases reported of PDHC deficiency have severe, lethal neonatal lactic acidosis with or without multiple congenital anomalies due to mutations in the X-linked E1alpha gene.

A 3 year old girl developed a cough and vomiting. Her 2 brothers recently suffered from the same symptoms. On the third day she became lethargic with rapid progression to coma. Hypoglycemia was noted, and the child made a full and rapid recovery upon resuscitative efforts in an emergency department.
Myopathy is absent. There is no significant past medical history, and the neurological examination and developmental milestones were normal. Among the following, the most likely diagnosis is:

A. Pyruvate dehydrogenase complex (PDHC) deficiency
B. MELAS
C. Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency
D. Long chain 3-hydroxyl acyl coenzyme A dehydrogenase (LCHAD) deficiency
E. Kearns-Sayre syndrome (KSS)

Correct: C.

Fasting-related acute brain dysfunction associated with common viral infections is a frequent presentation in all fatty acid oxidation disorders. Hypoglycemia is often present. Myopathy is commonly present in long-chain fatty acid disorders and absent in MCAD.

A 1 year old girl developed a cough and vomiting. Her 2 brothers recently suffered from the same symptoms, which have since resolved. On the third day, the patient became lethargic with rapid progression to coma.
Hypoglycemia was noted, and she made a full and rapid recovery upon resuscitative efforts in an emergency department. Hypotonia, muscle weakness and cardiomyopathy are present, but there is no past history of myopathy. Developmental milestones were normal. Among the following, the most likely diagnosis is:

A. Pyruvate dehydrogenase complex (PDHC) deficiency
B. MELAS
C. Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency
D. Long chain 3-hydroxyl acyl coenzyme A dehydrogenase (LCHAD) deficiency
E. Kearns-Sayre syndrome (KSS)

Correct: D

Fasting-related acute brain dysfunction associated with common viral infections is a frequent presentation in all
fatty acid oxidation disorders. Hypoglycemia is often present. Myopathy (muscle disease, including of the heart "cardiomyopathy") is commonly present in long-chain fatty acid disorders such as LCHAD deficiency.

A brother and sister presented in early infancy with moderate
developmental delay and a severe seizure disorder. No family members are affected. Muscle biopsy in the boy
supports the presence of a mitochondrial disorder. The recurrence risk in future siblings is most likely:

A. 25%
B. 50%
C. Undetermined, yet likely to be very high
D. Cannot determine from this information.

Correct: A.

Autosomal recessive mitochondrial disorders generally present with severe infantile-onset disease. As in other recessive disorders, siblings (including both males and females) generally are similarly affected.

A boy presents in early infancy with developmental delay and a severe seizure disorder, while his sister presents at age 10 years with a cardiomyopathy. The mother suffers from migraine headaches. Muscle biopsy in the boy supports the presence of a mitochondrial disorder. The recurrence risk in future siblings is most likely:

A. 25%
B. 50%
C. Undetermined, yet likely to be very high
D. Cannot determine from this information.

Correct: C.

Extreme variable expressivity is common in the maternal inheritance of mtDNA mutations. Disease onset of a mtDNA mutation can be at any age. If disease onset is after infancy in a patient with a mitochondrial disorder, then maternal inheritance is highly likely.

A 3 year old girl has severe neuromuscular disease. Diagnostic work-up reveals pyruvate dehydrogenase complex deficiency, and a frame shift mutation is found in one allele of the PDHC E1 alpha gene, resulting in a null allele (zero enzyme activity). If the parents had a boy with the same mutation, what would be the expected outcome? A. Severe lactic acidosis in the neonatal period B. About the same degree of severity as the female proband C. Any degree of severity is likely, from infantile lethal to a carrier D. No affected males would be expected due to early embryonic deathCorrect: D. Affected females with X-linked PDHC E1 alpha deficiency have null mutations and unfavorably skewed lyonization. These same null mutations cause embryonic lethality in hemizygous males.Protein synthesis for all mtDNA-encoded polypeptides is defective in which of the following mutations: A. G11778A, a primary LHON mutation in a complex 1 gene B. A8344G, MERRF mutation in the tRNA lysine gene C. A 7 kb deletion in the greater arc D. A and B above E. B and C aboveCorrect: E. Mutations in a transfer RNA gene result in the deficiency of all mtDNA-encoded proteins. Large deletions remove several transfer RNA genes.The co-existence of 2 or more mtDNA types in the same cell, tissue and organism is known as: A. Homoplasmy B. Heteroplasmy C. Diversity D. MutationBA boy with an unknown mitochondrial disease and a negative family history is how likely to have an affected child with the same condition: A. Essentially never (unless in a consanguineous union) B. Quite unlikely; a low recurrence risk should be given C. Estimated at 25% D. 0-100% - unable to determine.Correct: B. The less likely possibility of autosomal dominant inheritance is still possible.Most mtDNA disorders known are: A. Homoplasmic B. Heteroplasmic C. Near equal numbers of each of the above.BThe "bottleneck" phenomenon results in: A. The absence of clinical disease until mutant mtDNA levels reach a certain level. B. Sporadic disease in the case of a large mtDNA deletion. C. Varying proportions of mutant heteroplasmy among tissues in an affected individual. D. Often drastically varying proportions of mutant heteroplasmy among individuals in a family segregating a mtDNA mutation.Correct: D. The bottleneck refers to a small mtDNA copy number during pre-oocyte formation, resulting in different ova/zygotes having widely different proportions of mutant and wild-type heteroplasmy.Which of the following pairs involves 2 tissues with high- energy requirements and thus most expected to occur as a result of mitochondrial disease: A. Diabetes and renal tubular acidosis B. Epilepsy and chronic lung disease C. Skin dermatitis and cardiomyopathy D. Hypothyroidism and bone diseaseCorrect: A. In addition to neuromuscular disease, endocrine (hormonal) and renal tubular abnormalities are most commonly seen in mitochondrial disease.The following metabolites are markers for possible mitochondrial disease: A. Lactate and pyruvate B. Ketones C. 3-methylglutaconate D. Dicarboxylic acids (including ethylmalonate and glutarate) E. All of the aboveCorrect: E. All of the above when elevated are non-specific markers for the presence of mitochondrial disease.A child is suspected of having a maternally-inherited mitochondrial disease based upon clinical, laboratory and pedigree-based information. "Standard mtDNA analysis" was negative. Which of the following statements is most accurate: A. The patient does not have a mitochondrial disorder. B. The patient has a nuclear-encoded mitochondrial disorder(autosomal recessive, dominant or X-linked). C. Standard mtDNA testing is very insensitive, and mtDNA disease is present despite the test result. D. Could be any of the above; careful evaluation and a very detailed pedigree are indicated.Correct: D. Standard mtDNA analysis is positive in only a minority of cases with suspected maternally-inherited mitochondrial disease. Each of the above scenarios must be considered.Which statement best describes the current status of prenatal diagnosis for mitochondrial disease (not including fatty acid oxidation disorders): A. Prenatal diagnosis is impossible because of the complexity of heteroplasmy. B. With rare exceptions, prenatal diagnosis is unavailable for the vast majority of the families. C. Prenatal diagnosis is available in many cases, and unavailable in an almost equal number of cases. D. Prenatal diagnosis is available in most cases, and should always be offered to the families.Correct: B. The exceptions include some cases with the 8993G or C mtDNA mutation, and where mutations in nuclear- encoded genes are identified.Among these compounds often supplemented in certain individuals with mitochondrial disease, which compound carries long chain fatty acids across the mitochondrial inner membrane: A. Creatine B. Carnitine C. Co-enzyme Q10 ("Co-Q") D. RiboflavinBAmong these compounds often supplemented in certain individuals with mitochondrial disease, which compound serves as a reservoir for high-energy phosphate (energy) in muscle: A. Creatine B. Carnitine C. Co-enzyme Q10 ("Co-Q") D. RiboflavinAAmong these compounds often supplemented in certain individuals with mitochondrial disease, which compound shuttles electrons within the electron transport chain (to complex 3): A. Creatine B. Carnitine C. Co-enzyme Q10 ("Co-Q") D. RiboflavinCIn mitochondrial disease, exercise can: A. Precipitate rhabdomyolysis (muscle breakdown) B. Increase strength and endurance C. Both of the above; moderation and care are key.Correct: C. Exercise can be a powerful tool to decrease exercise intolerance, but over-exercise can be dangerous.Neonatal liver failure and encephalopathy (brain dysfunction) is most consistent with: A. mtDNA depletion syndrome B. Kearns-Sayre syndrome C. Leigh disease D. MELAS E. MERRFCorrect: A. Liver failure is one of the two most common presentations of depletion, the other is myopathy. Infantile onset and encephalopathy are common in both presentations.Migraine and multiple strokes or stroke-like episodes is most consistent with: A. mtDNA depletion syndrome B. Kearns-Sayre syndrome C. Leigh disease D. MELAS E. MERRFCorrect: D. Migraine and stroke is the typical presentation of MELAS.Ocular myopathy (weak eye muscles) and ataxia (unstable walking) is most consistent with: A. mtDNA depletion syndrome B. Kearns-Sayre syndrome C. Leigh disease D. MELAS E. MERRFCorrect: B. Ocular myopathy and ataxia are two of the cardinal features of Kearns-Sayre syndrome. The others are cardiac conduction defects, increased CSF protein and onset before age 20 yearsRespiratory dysfunction and cranial nerve abnormalities are most consistent with: A. mtDNA depletion syndrome B. Kearns-Sayre syndrome C. Leigh disease D. MELAS E. MERRFCorrect: C. Respiratory dysfunction and cranial nerve abnormalities are two of the cardinal features of Leigh disease. The others are ataxia and hyperintense signals on brain MR.mtDNA depletion and multiple deletions in the same individual are present in many cases of: A. MNGIE (mitochondrial neurogastrointestinal encephalopathy) B. Kearns-Sayre syndrome C. Pearson syndrome D. MELASCorrect: A. MNGIE is caused by mutations in the nuclear- encoded gene for thymidine phosphorylase. Imbalanced nucleotide pools lead to secondary mtDNA abnormalities, including depletion and multiple deletions.Homoplasmic mtDNA mutations are the cause of: A. NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) B. LHON (Leber Hereditary Optic Neuropathy) C. MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) D. MNGIE (mitochondrial neurogastrointestinal encephalopathy)Correct: B. Several homoplasmic mutations in complex 1 genes cause/predispose towards LHON.Sporadic or aminoglycoside (an antibiotic) associated hearing loss is associated with point mutations in which gene: A. tRNA-leu UUR (transfer RNA leucine) B. tRNA-ile (transfer RNA isoleucine) C. 12S rRNA (ribosomal RNA) D. SURF1Correct: C. A1555G in the 12S rRNA gene is the most commonly reported mtDNA mutation in deaf individuals.Moderate and high levels of T8993G or C heteroplasmy generally cause: A. NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) B. Kearns-Sayre syndrome and NARP C. LHON (Leber Hereditary Optic Neuropathy) and NARP D. Leigh disease and NARPCorrect: D. Very high mutant loads of T8993G/C (usually > 95%) generally result in Leigh disease, while moderately lesser mutant loads (usually 70-95%) generally result in NARP.Leigh disease is caused by deficiency of: A. Complex 1 B. Complex 4 C. Complex 5 (mtDNA mutation) D. Pyruvate dehydrogenase complex deficiency E. All of the aboveCorrect: E. There are many causes of Leigh disease including deficiencies of complexes 1, 2, 4 and 5 as well as PDHC deficiency. T8993G/C is a mutation in a mtDNA-encoded complex 5 gene.The most common clinical presentation of the A3243G mutation is: A. MELAS B. Diabetes C. Skeletal Myopathy D. DeafnessCorrect: B. About 1% of all diabetes is estimated to be due to A3243G. Another common presentation is adult-onset deafness.Mitochondrial disease is frequently: A. Progressive B. Intermittent C. Static (neither progressive nor improving] D. All of the aboveCorrect: D. Mitochondrial disease can be progressive, static or improve over time. Intermittent disease is common as energy supply and demand change over time, especially in response to illness.mtDNA mutations are: A. Maternally inherited B. Sporadic (new mutations) C. Secondary to nuclear DNA mutations D. A or B above E. All of the aboveCorrect: E. mtDNA mutations can be maternally inherited, sporadic or secondary to nuclear DNA mutations.SURF1 is an assembly protein in which mutations should be considered in infants with Leigh disease and deficiency of: A. Complex 1 (NADH dehydrogenase) B. Complex 4 (cytochrome c oxidase, "COX") C. Complex 5 (ATP synthase) D. Pyruvate dehydrogenase (PDHC) E. All of the aboveCorrect: B. SURF1 mutations are common causes of Leigh disease when complex 4 of the electron transport chain demonstrates low activity.Elevated CSF protein is most typically found in which mitochondrial disorder: A. Kearns-Sayre syndrome B. MELAS C. Leigh disease D. LHON (Leber Hereditary Optic Neuropathy) E. Pyruvate dehydrogenase complex deficiencyACyclic vomiting syndrome: A. Is caused by mutations in a nuclear-encoded mitochondrial gene B. Demonstrates maternal inheritance in a substantial proportion of cases C. Is caused by specific tRNA mutations D. All of the aboveCorrect: B. At least half of cases of cyclic vomiting syndrome demonstrate maternal inheritance. mtDNA sequence variants are reported in some cases, mostly in the D-loop.The control region (D-loop): A. Controls mtDNA replication B. Controls mtDNA transcription C. Has both highly conserved and highly polymorphic regions D. Contains sequence variations that have been implicated with disease E. All of the aboveEWhat of the following statements are true regarding mitochondrial protein import? A. Most mitochondrial proteins are encoded locally by the mtDNA, but 13 important peptides are nuclear-encoded and imported into mitochondria B. Deficiency in one or more mitochondrial DNA import proteins is known to cause clinical disease that is maternally inherited. C. Deficiency in one or more mitochondrial DNA import proteins is known to cause clinical disease that is autosomal recessive or X-linked in inheritance. D. A and B above E. A and C above.Correct: C. Mohr-Tranebjaerg syndrome (sensorineural deafness, dystonia, dysphagia, cortical blindness and paranoia) is an X- linked disorder caused by mutations in DDP1, which is involved in import.Friedreich Ataxia is a mitochondrial disorder because: A. The gene is encoded on the mtDNA B. The absent protein proofreads the mtDNA, and its absence resulting in multiple mtDNA deletions C. The absent protein is involved in mitochondrial iron metabolism, and its absence affects the synthesis and maintenance of the iron-sulfur clusters in some of the electron transport chain complexes D. The absent protein is a free-radical scavenger, and its absence results in a loss of integrity of the mitochondrial double membrane, leading to apoptosis.Correct: C. In addition, the mutation is an expansion of a tri-nucleotide repeat.Gamma polymerase mutations can lead to: A. A wide variety of brain and muscle disorders, like most mitochondrial disorders. B. Male sub-fertility in men and premature menopause in women. C. SANDO (Sensory Ataxia, Neuropathy, Dysarthria, Ophthalmoplegia). D. Progressive external ophthalmoplegia (PEO, eye muscle weakness) and parkinsonian symptoms E. All of the above.EWhich of the following is most true regarding the prevalence of mitochondrial disease: A. Mitochondrial disease consists of many very rare disorders, which together are rare or uncommon. B. No studies on prevalence have been performed as these studies are not feasible with current knowledge. C. Some studies have suggested that some mitochondrial disorders are among the most-common genetic disorders. D. The aggregate prevalence rate has been measured, and is very common. E. These studies, predominately performed in the United States, show conflicting results.Correct: C. This is especially true for the mutations associated with LHON and MELAS.The clinical manifestations of Menkes disease, a disorder of copper transport, overlap with those of mitochondrial disease because: A. of a coincidence, as both are neurological disorders. B. cytochrome C oxidase has a copper atom as a cofactor. C. PDHC has a copper atom as a cofactor. D. copper overload affects iron metabolism, and hence mitochondrial function. E. copper is needed for glycolysis.Correct: B. Without adequate copper, cytochrome oxidase, AKA complex IV of the electron transport chain, cannot function properly. Of course, other, non-mitochondrial systems require copper, and Menkes has other manifestations not related to mitochondrial function, such as connective tissue disease due to a need for copper in collagen metabolism.Autosomal dominant inheritance can result in mitochondrial disease in which of the following manners: A. Via a gain of function to a peptide that attacks the iron-sulfur clusters of the electron transport chain. B. For Krebs cycle enzymes, half of the normal enzymatic activity is not enough. C. For cytochrome C assembly proteins, half of the normal protein levels is not enough. D. By increasing errors as mutant POLG polymerases and proof- reads mtDNA. E. It can't, mitochondrial disease is never autosomal dominant.DDietary management in mitochondrial disease has the following goals: A. Preventing fasting-related symptomatology, with or without hypoglycemia. B. Shunting more electrons via complex I or via complex II. C. Prevention or treatment of mitochondrial disease-associated gastrointestinal dysmotility with smaller frequent low-fat feedings. D. A and C above. E. All of the above.EWhich one of the following clinical attributes is LEAST likely to suggest the possibility of mitochondrial disease: A. Mother and daughter are very similarly affected. B. The problem is gone whenever the patient gets to the specialist. C. Normal intelligence. D. Highly-variable disease manifestations between two siblings. E. Highly-consistent disease manifestations between two siblings.Correct: A. While mother and daughter are likely affected in disorders with maternal inheritance, extreme variable expressivity is expected.Which one of the following clinical attributes is LEAST likely to suggest the possibility of mitochondrial disease: A. Dysautonomia. B. Psychiatric manifestations. C. Stroke. D. Chronic pain. E. Cancer.Correct: E. Mutations in some mitochondrial proteins can predispose towards some rare tumor types, but in general cancer is not seen more frequently in these patients or families.An infant has birth defects, multi-system failure and lactic acidosis. Muscle biopsy revealed abnormal mitochondria. Which of the following statements are true about the likely diagnosis: A. This baby has a congenital lactic acidosis (a mitochondrial disorder) such as deficiency of PDHC or cytochrome C, and no other condition fits this description. B. The baby may have one of the above disorders, but this baby may also have glutaric acidemia type II. C. The baby may have any of the above disorders, but this baby might also have a peroxisomal disorder (Zellweger syndrome). D. The baby may have any of the above disorders, but this baby might also have a chromosomal anomaly. E. This baby may have A, B or D, but not C.Correct: D. In particular, several chromosomal abnormalities can mimic mitochondrial disease, probably due to the involvement of nuclear-encoded mitochondrial proteins in the affected chromosomal segments.