Mitochondrial Dna Depletion Syndrome 5 (Encephalomyopathic With Or Without Methylmalonic Aciduria)

A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-5 (MTDPS5) is caused by homozygous or compound heterozygous mutation in the beta subunit of the succinate-CoA ligase gene (SUCLA2; 603921) on chromosome 13q14.

See MTDPS9 (245400) for a description of a similar disorder caused by mutation in the alpha subunit of the succinate-CoA ligase gene (SUCLG1; 611224).

Description

Mitochondrial DNA depletion syndrome-5 is an autosomal recessive disorder characterized by infantile onset of hypotonia, progressive neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, and variable renal tubular dysfunction. Laboratory studies often show mild methylmalonic aciduria (Carrozzo et al., 2007).

For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).

Clinical Features

Elpeleg et al. (2005) reported a small Muslim pedigree with an autosomal recessive encephalomyopathy associated with mtDNA depletion. The proband showed irritability and inconsolable crying in early infancy. She had severely delayed psychomotor development with marked muscle hypotonia, impaired hearing, and generalized seizures. Brain MRI was suggestive of Leigh syndrome (256000). At age 7 years, she was severely retarded and had contractures of the knee and hip joints. An affected cousin had muscle hypotonia, lack of voluntary movements, bilateral hearing loss, generalized seizures, and severe psychomotor retardation. Liver and renal tests in both patients were normal. Urinary organic acid profiles were not reported.

Ostergaard et al. (2007) reported 10 patients from the Faroe Islands with encephalomyopathic mtDNA depletion associated with mild methylmalonic aciduria. The clinical phenotype comprised infantile-onset hypotonia, muscle atrophy, hyperkinesias, severe hearing impairment, postnatal growth retardation, and lactic acidosis. Most patients had scoliosis or kyphosis, recurrent airway infections, and required tube feeding due to swallowing difficulties. Neuroimaging showed demyelination and central and cortical atrophy; some patients fulfilled the criteria for Leigh syndrome.

Carrozzo et al. (2007) also reported 11 patients from 8 related families in the Faroe Islands with neonatal onset of encephalomyopathy. Ten of the patients were in the report of Ostergaard et al. (2007) (Chinnery, 2007). Affected patients had feeding problems since birth and showed failure to thrive. Other features included severe muscle hypotonia with progressive areflexia, profound motor developmental delay, and none learned to sit or stand without support. They had progressive neurologic deterioration from the age of 12 to 14 months, and developed a hyperkinetic-dystonic movement disorder with external ophthalmoplegia. All developed profound sensorineural deafness. One had seizures, 2 had polyneuropathy, 1 had mild cardiomyopathy, and 1 had renal tubular dysfunction. Six patients died as children due to infection. Brain MRI showed hyperintense lesions in the basal ganglia. Laboratory studies showed mild methylmalonic aciduria, methylglutaconic aciduria, increased urinary carnitine esters, increased lactic acid in blood and CSF, and combined deficiencies of mitochondrial respiratory chain enzymes. SUCLA2 activity and protein were decreased in patient muscle.

Carrozzo et al. (2007) reported 3 additional patients from southern Italy with a similar phenotype, including infantile onset of hypotonia and severely delayed development associated with deafness and dystonic posturing.

Jaberi et al. (2013) reported 2 Iranian cousins with early-onset encephalomyopathy. One was a 4-year-old girl with delayed motor milestones, failure to thrive due to poor feeding, severe hypotonia with an inability to walk, severe generalized dystonia, and hearing loss. The second child was a 10-year-old girl who first showed progressive problems in gait and dystonia around age 3 years. She also had hearing loss and severe bulbar dystonia. Brain MRI of both patients showed T2-weighted hyperintensities in the caudate and putamen. Laboratory studies in 1 patient showed increased lactate and succinylcarnitine, but methylmalonic acid levels were normal. Muscle tissue was not available for mtDNA analysis.

Inheritance

The transmission pattern of MTDPS5 in the family reported by Jaberi et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

Elpeleg et al. (2005) identified a homozygous mutation in the SUCLA2 gene (603921.0001) in 2 first cousins from a consanguineous Muslim family with encephalomyopathy and mitochondrial DNA depletion syndrome-5. Urinary organic acid profiles were not reported in the patients studied by Elpeleg et al. (2005). SUCLA2 encodes succinyl-CoA synthase, an enzyme in the Krebs cycle, that is also involved in the salvage pathway of deoxyribonucleotides during mtDNA synthesis. Elpeleg et al. (2005) hypothesized that mtDNA depletion was likely explained by decreased mitochondrial NDP kinase (NDPK; see 156491) activity, resulting from the inability of NDPK to form a complex with SUCLA2.

In a total of 16 patients from the Faroe Islands with encephalomyopathic mitochondrial DNA depletion and mild methylmalonic aciduria, Ostergaard et al. (2007) and Carrozzo et al. (2007) independently identified a homozygous founder mutation in the SUCLA2 gene (603921.0002). Carrozzo et al. (2007) identified 2 additional SUCLA2 mutations (603921.0003; 603921.0004) in southern Italian patients with a similar disorder.

In 2 Iranian cousins with encephalomyopathy, Jaberi et al. (2013) identified a homozygous mutation in the SUCLA2 gene (D251N; 603921.0005). The mutation was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder, and was not present in 200 ethnically matched control individuals. Molecular modeling suggested that the mutation may cause structural changes that affect protein function. Functional studies were not performed.

Population Genetics

Ostergaard et al. (2007) estimated the incidence of the encephalomyopathic form of mtDNA depletion syndrome with methylmalonic aciduria in the Faroe Islands to be 1 in 1,700.

Carrozzo et al. (2007) estimated the carrier and disease frequencies in the Faroe Island population to be 2% and 1 in 2,500, respectively.