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Uniparental Disomy Causing Myoclonus Dystonia Associated with Russell Silver Syndrome

Myoclonus dystonia (MD) is a rare movement disorder characterized by alcohol-responsive myoclonic jerks, dystonia, and psychiatric complaints, which is often associated with an autosomal-dominant pathogenic variant (mutation) in the epsilon-sarcoglycan gene (SGCE), located on chromosome 7q21.3. Russell Silver syndrome (RSS) is a genetic condition characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry, triangular facies, café au lait spots, and dysmorphic features, most often caused by hypomethylation of the paternal imprinting center 1 of chromosome 11p15.5 or maternal uniparental disomy for chromosome 7 (mUPD7). We describe a patient with myoclonus dystonia-like syndrome because of mUPD7 associated with RSS, rather than the SGCE pathogenic variant. An 18-year-old right-handed woman with a history of RSS, panic attacks, and depression presented for evaluation of abnormal movements. She was born prematurely at 35 weeks, with pregnancy complicated by intrauterine growth retardation. At birth, she was noted to be of low birth weight and height (<2nd percentile at birth and 7 and 17 months) with preserved head circumference. She also had a history of motor delay. At age 13 years, she developed body jerks affecting the head and extremities. The movements were not suppressible or associated with a premonitory sensation. The patient also reported arching of the back and spasms in the lower extremities with walking, as well as difficulty holding onto objects. Multiple medications, including topiramate, escitalopram, risperidone, gabapentin, propranolol, and tetrabenazine, were ineffective. Family history, imaging, and electroencephalogram were unremarkable. On examination, she was found to have a small, triangular face, prominent forehead, enlarged earlobes with low-set ears, short arms, clinodactyly bilaterally, and café au lait spots on the trunk. Neurological examination showed generalized actioninduced myoclonus of the head and all extremities and dystonic posturing of the upper and lower extremities, neck, and trunk. A single-nucleotide polymorphism array showed 2 segments of homozygosity on chromosome 7 totaling 65 MB in size, suggesting uniparental disomy of chromosome 7, which was confirmed by polymer chain reaction-based microsatellite marker analysis of the patient and her parents. SGCE mutation testing did not reveal any pathogenic variants. MD is associated with autosomal-dominant loss-of-function pathogenic variants in the SGCE gene located on chromosome 7q21.3, a maternally imprinted (silenced) gene. In up to 10% of cases, RSS is associated with mUPD7, in which patients have 2 copies of the maternal allele for chromosome 7 rather than one from each parent. This is the 5th reported case of a patient with clinical features of both disorders, absence of variants in SGCE, and genetic analysis showing mUPD7. mUPD7 has also been reported to have an association with other movement disorders, specifically head and upper extremity tremor. We hypothesize that mUPD7 may lead to the MD phenotype because of lack of expression of SGCE in the absence of a paternal allele (because both maternal alleles are typically silenced). Given reports of cases with both phenotypes and given the underlying genetic etiology, individuals with MD and short stature should be routinely evaluated for RSS, and individuals with RSS and mUPD7 should be assessed for MD.