Mitochondrial Dna Depletion Syndrome 7 (MTDPS7)

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Disease Ontology 12 DOID:0080126 OMIM® 57 271245 OMIM Phenotypic Series 57 PS603041 MeSH 44 C535523 D020754 MESH via Orphanet 45 C535523 ICD10 via Orphanet 33 E88.8 G11.1

UMLS via Orphanet 71 C1849096 Orphanet 58 ORPHA1186 ORPHA363534 MedGen 41 C1849096 SNOMED-CT via HPO 68 103276001 15188001 16110005 166603001 166643006 228156007 230456007 241006 247578003 252157006 255314001 258211005 26544005 271782001 278849000 343087000 349006 370999003 37280007 37796009 398151007 398152000 412786000 44913001 563001 58593005 69322001 7006003 75183008 76976005 79519003 81308009 85102008 91138005 95646004 95828007 more UMLS 70 C1837454 C1849096

GARD : ²⁰ The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 1186 Definition Infantile-onset spinocerebellar ataxia (IOSCA) is a hereditary neurological disorder with early and severe involvement of both the peripheral and central nervous systems. It has only been described in Finnish families. Epidemiology So far, 24 cases have been reported. In Finland, IOSCA has a population carrier frequency of more than 1:230. Clinical description IOSCA is characterized by very early ataxia, athetosis and reduced tendon reflexes (between 9 and 18 months of age). Ophthalmoplegia and sensorineural hearing loss are diagnosed in childhood. Other features, such as optic atrophy and sensory neuropathy with progressive loss of myelinated fibers in the sural nerve, appear later in the disease course. Hypogonadism may occur in females. Some patients show intellectual deficit. Epilepsy is a late manifestation and seizures may be life-threatening. Etiology IOSCA is caused by mutations in the C10orf2 gene (10q24) encoding the mitochondrial helicase Twinkle. The c.1523A>G (p.Y508C) causative mutation has been postulated to be a founder mutation. Twenty-one of the reported patients were homozygous for this mutation, and three were compound heterozygotes : c.952G>A/c.1523A>G (two patients) and c.1523A>G/c.1287C>T (one patient). The mutations lead to mtDNA depletion in the brain and the liver, but not in the muscle. Diagnostic methods The diagnosis is based on clinical and pathological findings. Studies of sural nerve biopsies reveal an early and rapidly progressive axonal neuropathy. Neuroimaging studies revealing cerebellar atrophy and genetic testing for the c.1523A>G mutation may also help to confirm the diagnosis. Differential diagnosis Differential diagnoses include early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy, mitochondrial disorders with axonal neuropathy (such as Friedreich ataxia), progressive external ophthalmoplegia (PEO), juvenile- or adult-onset mitochondrial recessive ataxia syndrome (MIRAS), and POLG -related disorders (see theseterms). Antenatal diagnosis Prenatal testing may be available for families in which the disease-causing mutations have already been identified. Genetic counseling IOSCA is inherited in an autosomal recessive manner. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child: the risk of having an affected child in further pregnancies is 25%. Management and treatment IOSCA patients are often managed by a multidisciplinary team, involving a pediatrician, neurologist, psychiatrist, orthopedic surgeon, physical and occupational therapists, genetic counselor, and social worker. Treatment is symptomatic and may include: (1) hearing aids, speech therapy and sign language for deafness; (2) physical therapy, orthotic devices and orthopedic surgery for sensory axonal neuropathy; (3) walking aids, a wheelchair, physiotherapy and occupational therapy for ataxia; (4) antiepileptic drugs for seizures and (5) antipsychotics and antidepressants for psychiatric symptoms. Prognosis Prognosis is unfavorable. Patients are wheelchair-bound by adolescence. Early death is common due to severe seizures. The clinical course seems to be more rapid and severe (with death during infancy) in c.952G>A/ c.1523A>G compound heterozygotes.

MalaCards based summary : Mitochondrial Dna Depletion Syndrome 7, also known as infantile onset spinocerebellar ataxia, is related to dysphagia and axonal neuropathy, and has symptoms including ataxia, tremor and muscle weakness. An important gene associated with Mitochondrial Dna Depletion Syndrome 7 is TWNK (Twinkle MtDNA Helicase), and among its related pathways/superpathways are Spinocerebellar ataxia and Mitochondrial Gene Expression. Affiliated tissues include eye, liver and cerebellum, and related phenotypes are ataxia and hearing impairment

Disease Ontology : ¹² A mitochondrial DNA depletion syndrome that is characterized by progressive ataxia, hypotonia, hyporeflexia, athetosis and sensory impairment and has material basis in autosomal recessive homozygous or compound heterozygous mutation in the C10ORF2 gene, which encodes the twinkle and twinky proteins, on chromosome 10q24.

MedlinePlus Genetics : ⁴³ Infantile-onset spinocerebellar ataxia (IOSCA) is a progressive disorder that affects the nervous system. Babies with IOSCA develop normally during the first year of life. During early childhood, however, they begin experiencing difficulty coordinating movements (ataxia); very weak muscle tone (hypotonia); involuntary writhing movements of the limbs (athetosis); and decreased reflexes. By their teenage years affected individuals require wheelchair assistance.People with IOSCA often develop problems with the autonomic nervous system, which controls involuntary body functions. As a result, they may experience excessive sweating, difficulty controlling urination, and severe constipation.IOSCA also leads to vision and hearing problems that begin by about age 7. Children with this disorder develop weakness in the muscles that control eye movement (ophthalmoplegia). In their teenage years they experience degeneration of the nerves that carry information from the eyes to the brain (optic atrophy), which can result in vision loss. Hearing loss caused by nerve damage (sensorineural hearing loss) typically occurs during childhood and progresses to profound deafness.Individuals with IOSCA may have recurrent seizures (epilepsy). These seizures can lead to severe brain dysfunction (encephalopathy).Most people with IOSCA survive into adulthood. However, a few individuals with IOSCA have an especially severe form of the disorder involving liver damage and encephalopathy that develops during early childhood. These children do not generally live past age 5.

OMIM® : ⁵⁷ Mitochondrial DNA depletion syndrome-7 is an autosomal recessive severe neurodegenerative disorder characterized primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy. Although originally classified as a form of spinocerebellar ataxia (see, e.g., SCA1, 164400) (Koskinen et al., 1994), it has been reclassified as a mitochondrial DNA depletion syndrome (Hakonen et al., 2008) based on the finding of mtDNA depletion in the brain and liver of affected individuals. For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041). (271245) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : ⁷² Mitochondrial DNA depletion syndrome 7: A severe disease associated with mitochondrial dysfunction. Some patients are affected by progressive atrophy of the cerebellum, brain stem, the spinal cord, and sensory axonal neuropathy. Clinical features include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural hearing deficit, sensory axonal neuropathy, epileptic encephalopathy and female hypogonadism. In some individuals liver dysfunction and multi-organ failure is present.

GeneReviews: NBK3795

Clinical features from OMIM®:

271245 (Updated 05-Apr-2021)

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