Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing

Murphy, Sinéad M.; Laurá, Matilde; Fawcett, Katherine A.; Pandraud, Amelie; Liu, Yo‐Tsen; Davidson, Gabrielle L.; Rossor, Alexander M.; Polke, James M.; Castleman, Victoria; Manji, Hadi; Lunn, Michael P.; Bull, Karen; Ramdharry, Gita; Davis, Mary B.; Blake, Julian; Houlden, Henry; Reilly, Mary M.

doi:10.1136/jnnp-2012-302451

Cited by 305 publications

(349 citation statements)

References 27 publications

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“…15,16 Interestingly, GDAP1, the most frequent genetic cause for CMT4, encodes a protein anchored to the mitochondrial outer membrane, thus demonstrating that mitochondrial disorders may manifest with demyelinating polyneuropathy as the predominant feature. 1,[15][16][17] The SURF1 gene encodes one of at least 6 assembly factors of COX, the terminal component of the MRC. Studies on yeast and human mutant cells indicate for SURF1 a role in the formation of the early subcomplexes of COX.…”

Section: Characteristics Of the Cmt4 Index Familymentioning

confidence: 99%

“…This finding is relevant because molecular defects are currently detected in less than 20% of CMT4 patients. 14,15 In both families, a mitochondrial etiology of the disease had not been initially considered because the phenotype consisted of isolated peripheral neuropathy, with very little additional multisystem involvement.…”

Section: Characteristics Of the Cmt4 Index Familymentioning

confidence: 99%

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SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

et al. 2013

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Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-MarieTooth (CMT) disease. Methods:We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A.G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A.G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities ,25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A.G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions:We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. Peripheral neuropathies are a well-known complication of mitochondrial DNA and nuclearencoded mitochondrial gene mutations. For instance, patients with mutations in the nuclearencoded mitochondrial genes MFN2 and GDAP1, which encode outer mitochondrial membrane proteins, usually present with axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease, respectively.1 Moreover, patients with mutations in the mitochondrial DNA gene MTATP6, which encodes the ATP6 subunit of the mitochondrial respiratory chain (MRC) complex V, may present with axonal CMT (CMT2). 2The determination of the genetic cause is a major challenge in rare neuromuscular diseases such as autosomal recessive demyelinating CMT (CMT4). We investigated a consanguineous family in which 2 patients with CMT4 harbored a homozygous splice site mutation in SURF1, encoding an assembly factor of the MRC complex IV (cytochrome c oxidase [COX]). Despite this defect, we detected some residual assembly and function of COX in fibroblasts and muscle of both patients. We then screened for SURF1 mutations in a cohort of 40 unrelated patients

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Section: Characteristics Of the Cmt4 Index Familymentioning

confidence: 99%

Section: Characteristics Of the Cmt4 Index Familymentioning

confidence: 99%

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

et al. 2013

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“…More recent studies in large cohorts of patients confirmed that most CMTs are demyelinating but lowered its prevalence to approximately half of all cases, while the prevalence of axonal forms was assessed to be less than one-third, i.e. 17.6-27.1% [Foley et al, 2012;Murphy et al, 2012]. Moreover, the proportion of axonal or demyelinating CMT seems to depend on the geographical area, the structure of the population and the frequency of CMT in the general population.…”

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confidence: 99%

Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

Azzedine

Senderek²,

Rivolta³

et al. 2012

Mol Syndromol

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Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders of the peripheral nervous system, mainly characterized by distal muscle weakness and atrophy leading to motor handicap. With an estimated prevalence of 1 in 2,500, this condition is one of the most commonly inherited neurological disorders. Mutations in more than 30 genes affecting glial and/or neuronal functions have been associated with different forms of CMT leading to a substantial improvement in diagnostics of the disease and in the understanding of implicated pathophysiological mechanisms. However, recent data from systematic genetic screening performed in large cohorts of CMT patients indicated that molecular diagnosis could be established only in ∼50–70% of them, suggesting that additional genes are involved in this disease. In addition to providing an overview of genetic and functional data concerning various CMT forms, this review focuses on recent data generated through the use of highly parallel genetic technologies (SNP chips, sequence capture and next-generation DNA sequencing) in CMT families, and the current and future impact of these technologies on gene discovery and diagnostics of CMTs.

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“…As Fig. 1 shows, once the mode of inheritance was taken under consideration, searching for the relevant mutations covered most of the mutations in the studied population (10 ).…”

Section: Discussionmentioning

confidence: 99%

Increased Serum Creatine Kinase

Mirzazadeh

Maghsoodi

Barron³

2014

Clinical Chemistry

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A 38-year-old white male taxi driver was referred to a lipid clinic by his general practitioner for management of combined hyperlipidemia. He was a smoker with a 20 packyear history. His father had died of myocardial infarction at age 55 years. Examination of this patient revealed a blood pressure of 136/99 mmHg and a body mass index of 29 kg/m 2 , with no clinical signs of hyperlipidemia. Cholesterol testing revealed a total serum cholesterol value of 251 mg/dL (6.5 mmol/L; reference interval, 3.7-7.0 mmol/L), an HDL concentration of 30.9 mg/dL (0.8 mmol/L; reference interval, 0.7-1.8 mmol/L), and triglycerides of 539 mg/dL (6.1 mmol/L; reference interval, Ͻ1.7 mmol/L), results consistent with metabolic syndrome. The patient's calculated 10-year cardiovascular risk was Ͼ20%, indicative for primary prevention of hyperlipidemia with a statin, after changes in lifestyle (1 ). Baseline biochemical investigations before starting the statin showed a serum creatine kinase (CK) 4 activity of 889 U/L (reference interval, 24 -195 U/L) and an alanine aminotransferase activity of 61 U/L (reference interval, Ͻ50 U/L). The results of other tests were within their respective reference intervals: total bilirubin, 0.8 mg/dL (13 mol/L; reference interval, Ͻ14 mol/L); alkaline phosphatase, 95 U/L (reference interval, Ͻ150 U/L); and ␥-glutamyltransferase, 49 U/L (reference interval, Ͻ50 U/L). The results of other laboratory investigations (including renal function, blood count, serum vitamin B 12 , folate, serum protein electrophoresis, antinuclear antibodies, C-reactive protein, and thyroid function) were normal. At 30 years of age, the patient's mother had been diagnosed with lower limb muscle weakness, which made her unable to dorsiflex her feet. His 48-year-old brother and 38-year-old maternal half-brother were both fine.On questioning, the patient admitted to a weekend of heavy physical activity before the test but had no other major complaints. PATIENT FOLLOW-UPAt this point, the most likely cause of the increased serum CK activity was heavy exercise; however, after a week of lower physical activity, the patient's serum CK activity was still increased at 737 U/L.Owing to the persistently increased serum CK, the patient was referred for metabolic investigations, including the ischemic forearm test, plasma and urinary amino acids, and a plasma carnitine profile. The test results for amino acids and the carnitine profile were all normal.The ischemic forearm test showed a borderline increase in ammonia that was lower than expected, along with a normal increase in lactate concentration. These results suggested the possibility of heterozygous myoadenylate deaminase (MADA) deficiency.During his visit for the ischemic forearm test, a steppage gait was observed. On questioning, the patient admitted that he had been aware of slightly weak legs all his life. He was referred for electromyography (EMG) testing, nerve conduction velocity (NCV) studies, and neurology and genetics services, with a working diagnosis of hereditary sensory mot...

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Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing

Cited by 305 publications

References 27 publications

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

Increased Serum Creatine Kinase

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