Mitochondrial Membrane Protein-Associated Neurodegeneration

Clinical Characteristics: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.
Diagnosis/testing: The diagnosis of MPAN is typically established in a proband with suggestive findings and biallelic pathogenic variants (or less commonly a heterozygous pathogenic variant) in C19orf12 identified by molecular genetic testing.
Management: Treatment of manifestations: Pharmacologic treatment of spasticity, dystonia, and parkinsonism; psychiatric treatment of significant neuropsychiatric manifestations; physical, occupational, speech, and other therapies as indicated; nutritional supplements and gastric tube feeding as needed; management of excessive secretions and aspiration risk with glycopyrrolate, transdermal scopolamine patch, and/or tracheostomy as indicated. Surveillance: Routine follow up by a neurologist for medication management and interval assessment of ambulation, speech, and swallowing (often done every 3-6 months, but may be annual for individuals who are more stable); routine monitoring by occupational therapy / physical therapy, mental health providers, ophthalmology, speech and language therapy, and feeding team is recommended; routine assessment of educational needs and social support.
Genetic Counseling: MPAN is inherited in an autosomal recessive or (less commonly) autosomal dominant manner. Autosomal recessive MPAN. If both parents are known to be heterozygous for an C19orf12 pathogenic variant, each sib of an affected individual has at conception 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. Autosomal dominant MPAN. Each child of an affected individual has a 50% chance of inheriting the C19orf12 pathogenic variant. Once the C19orf12 pathogenic variant(s) in the family have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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