Myoclonus-dystonia: An under-recognized entity - Report of 5 cases
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.190255
Source of Support: None, Conflict of Interest: None
Keywords: Dystonia-plus; DYT 11; epsilon-sarcoglycan; myoclonus-dystonia; primary dystonia
Hereditary myoclonus-dystonia (DYT 11) is caused by an epsilon-sarcoglycan (SGCE) mutation (chromosome 7q21), first described in 2001. A positive family history is usually present, but sporadic cases due to de novo mutations or maternal-imprinting have also been described. We describe 5 patients (3 families) with myoclonus-dystonia diagnosed at our center.
A 12-year-old girl presented with daily, multiple episodes of jerky body movements since 2-years of age. The jerks predominantly involved lower limbs and trunk, especially while walking (causing occasional falls) [Video 1], and upper limbs and head and neck region, while writing or drinking water. They were occasionally present at rest and absent during sleep. The frequency of the jerks had remained stable over the years. There was also a history of abnormal twisting of hands while writing, resulting in deterioration of the handwriting. She had normal cognition, behavior, hearing, and vision.
Her younger sister, a 9-year-old child, had similar problems but showed a more severe hand-dyskinesia [Video 2 and 3]. The father, aged 45-year, had action-myoclonus affecting the upper-limb and head and neck region since the third decade of life, which was now improving. The jerks were only visible while shaving or writing. He also had a mild cervical dystonia. The response to alcohol was unknown as he was nonalcoholic.
Examination of the siblings was normal except for mild dystonias present in the hands while writing. Magnetic resonance imaging (MRI) of the brain, as well as ictal and interictal electroencephalogram (EEG) were normal. Wilson disease work-up, arterial blood-gas, lactate, ammonia, blood sugar, urine ketones, plasma acylcarnitine profile, and urinary organic acid analysis were normal.
With the background of predominant action myoclonus and relatively mild dystonias in cognitively-preserved children, a possibility of myoclonus-dystonia (DYT 11) was considered. The two affected siblings and father were heterozygous for the novel SGCE-gene-mutations [Figure 1]. The siblings showed a poor response to clonazepam, trihexyphenidyl, and tetrabenazine.
The index patient was a 5-year-old boy who had daily, multiple, jerky body movements. These affected upper limbs and head and neck region while writing, eating or drinking water since 3.5-years of age. The jerks were absent at rest and during sleep. In addition, he also had abnormal twisting of hands while writing. His development, hearing, and vision were normal, and he did not have any behavioral problems. There was no significant family history. Examination revealed mild dyskinesia of the hands while writing. MRI brain as well as ictal and interictal EEG were normal. The investigations to rule out secondary causes (as described in the previous case) were normal.
The affected child and his father were heterozygous for the novel SGCE-gene mutations [Figure 1]. The child had a partial response to clonazepam with a mild decrease in the frequency of myoclonus.
The index patient was a 4-year-old boy, who had daily, multiple, jerky body movements present since 3 years of age. These affected the upper limbs and head and neck region while writing, eating or drinking water [Video 4]. The jerks were absent at rest and during sleep. There was no history of other seizure types or abnormal posturing/twisting. He had a normal development with preserved hearing, vision, and cognition. There was no significant family history or history of measles.
Examination also revealed mild dyskinesia of the hands while writing. MRI brain as well as ictal and interictal EEG were normal. The investigations to rule out secondary causes were normal.
No pathogenic variant in the SGCE-gene was detected in the child or his parents. The child had a good response to clonazepam. A provisional diagnosis of SGCE-negative myoclonus-dystonia was made.
The clinical details of the reported cases have been summarized in [Table 1].
The typical phenotype in myoclonus-dystonia consists of rest or action-myoclonus (usually alcohol-responsive), either alone or associated with mild to moderate dystonia. The symptoms generally predominate in the upper body. All our patients had action myoclonus. The two affected sisters had rest myoclonus as well. Lower-limb myoclonus was present in the two girls in family-1. Lower-limbs have been reported to be involved in 25% of cases, and girls are more likely to have onset in the legs. Myoclonus seems to be generated at the sub-cortical level explaining the normal ictal EEGs.
At presentation, the dystonia is usually mild-to-moderate with cervical-dystonia and writer's cramp being common. Psychiatric disturbances have been reported in some families with myoclonus-dystonia., None of our patients showed any significant behavioral problems. Similar observations were reported previously in a French cohort.
The course of myoclonus and dystonia is variable. Both worsening and spontaneous remission have been described. The father in family-1 had gradual improvement in both myoclonus and dystonia. The affected children will require prolonged follow-up to study the disease course and treatment response.
Family-1 also displayed intrafamilial phenotypic variability. Both the affected sisters had an early onset of symptoms, and their father had his symptom onset in the third decade. Usually, the onset of symptoms in myoclonus-dystonia is in the first or second decade of life,, however, late-onset symptoms have been described.,
Sequence analysis of the SGCE-gene in family-1 showed that both the affected children and their father carried a novel mutant variant in the SGCE-gene. The paternal grandparents did not carry this variant. The variant seems to be a de novo variant, first presented in the father and then inherited by his children. In family-2, both the index case and the father were carrying the mutant variant in the SGCE-gene. This mutation has not been described earlier. Since SGCE-gene is maternally imprinted, it might be that the father had inherited the allele from his mother explaining the fact that he has no clinical signs of myoclonus-dystonia. Unfortunately, the paternal grandparents could not be tested.
In patients with typical myoclonus-dystonia phenotype, the mutation detection rate in the SGCE-gene is nearly 50%. The affected child in family-3 had a typical phenotype but was SGCE-negative. This suggests that myoclonus-dystonia is genetically heterogeneous. Involvement of other genes, still unidentified pathogenic SGCE-mutations or epigenetic defects may be possible.
Myoclonus may be observed in other primary dystonias, including DYT 1 and DYT 5 dystonia. Sometimes, dystonia and jerky choreic movements due to benign-hereditary-chorea may be difficult to distinguish clinically from myoclonus-dystonia. A new entity called “limb dystonia with poly-mini myoclonus” has been described in a few SGCE-negative patients. Other reported entities mimicking myoclonus-dystonia rarely include spinocerebellar ataxia type 14, guanosine triphosphate cyclohydrolase deficiency, and isolated vitamin-E-deficiency.
When myoclonus and dystonia are only part of the phenotype, mitochondrial disorders, Lafora-body-disease, GM2-gangliosidosis, Niemann-Pick disease, and tyrosine hydroxylase deficiency  should be considered in the differential diagnosis.
Thus, a diagnosis of myoclonus-dystonia should be considered in cognitively normal patients with early onset myoclonus (rest and/or action) with or without dystonia and with or without psychiatric disturbances. They should be tested for SGCE-mutations even if the family history is absent.
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