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CASE REPORT
Year : 2016  |  Volume : 64  |  Issue : 5  |  Page : 980-983

Myoclonus-dystonia: An under-recognized entity - Report of 5 cases


1 Department of Neonatology, Pediatric and Adolescent Medicine, Division of Pediatric Neurology, BL Kapur Super Speciality Hospital, New Delhi, India
2 Department of Pediatrics, Division of Pediatric Neurology, Lady Harding Medical College and Associated Kalawati Saran Children Hospital, New Delhi, India
3 Department of Genome Analysis, Academic Medical Centre, Laboratory for Neurogenetics, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands

Date of Web Publication12-Sep-2016

Correspondence Address:
Puneet Jain
Department of Neonatology, Division of Pediatric Neurology, Pediatric and Adolescent Medicine, BL Kapur Super Speciality Hospital, Pusa Road, New Delhi - 110 005
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.190255

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 » Abstract 


Hereditary myoclonus-dystonia (DYT 11) is caused by the epsilon-sarcoglycan (SGCE) mutation. The clinical details and investigations of cases diagnosed with myoclonus-dystonia were reviewed. We describe 5 patients (3 families) with myoclonus-dystonia diagnosed at our center. Majority of the patients had the classical phenotype with few atypical features (adult-onset disease and onset in lower limbs). Four patients carried a mutant variant in the SGCE-gene. A diagnosis of myoclonus-dystonia should be considered in cognitively normal patients with early-onset myoclonus (that may occur both at rest and/or action) with or without dystonia and with or without psychiatric-disturbances.


Keywords: Dystonia-plus; DYT 11; epsilon-sarcoglycan; myoclonus-dystonia; primary dystonia


How to cite this article:
Jain P, Sharma S, van Ruissen F, Aneja S. Myoclonus-dystonia: An under-recognized entity - Report of 5 cases. Neurol India 2016;64:980-3

How to cite this URL:
Jain P, Sharma S, van Ruissen F, Aneja S. Myoclonus-dystonia: An under-recognized entity - Report of 5 cases. Neurol India [serial online] 2016 [cited 2019 Nov 15];64:980-3. Available from: http://www.neurologyindia.com/text.asp?2016/64/5/980/190255





 » Introduction Top


Hereditary myoclonus-dystonia (DYT 11) is caused by an epsilon-sarcoglycan (SGCE) mutation (chromosome 7q21), first described in 2001.[1] A positive family history is usually present, but sporadic cases due to de novo mutations or maternal-imprinting have also been described.[2] We describe 5 patients (3 families) with myoclonus-dystonia diagnosed at our center.


 » Case Reports Top


Family-1

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.
Figure 1: Representation of the two families (1 and 2) in which we identified two novel epsilon-sarcoglycan mutations. In the left panel, the pedigree of family-1 is shown. The two affected siblings and father (affected members colored in black) were heterozygous for the c.101T>C nucleotide change (p.Leu34Ser) in the epsilon-sarcoglycan gene (reference-sequence NM_003919.2). No deletions or duplications were found in the epsilon-sarcoglycan gene. No pathogenic variant in the epsilon-sarcoglycan gene was detected in the mother and the paternal grandparents. The electropherograms of corresponding family members are shown underneath. In the right panel, the pedigree of family-2 is shown. The affected child and his father (affected members colored in black) were heterozygous for the c.347G>A nucleotide change (p.Glyll6Glu) in the epsilon-sarcoglycan gene (reference-sequence NM_003919.2). No deletions or duplications were found in the epsilon-sarcoglycan gene. No pathogenic variant in the epsilon-sarcoglycan gene was detected in the mother. The grandparents were not available for testing. The electropherograms of corresponding family members are shown underneath

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Family-2

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.

Family-3

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].
Table 1: Summary of cases diagnosed as myoclonus-dystonia

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 » Discussion Top


The typical phenotype in myoclonus-dystonia consists of rest or action-myoclonus (usually alcohol-responsive), either alone or associated with mild to moderate dystonia.[2] 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,[2] and girls are more likely to have onset in the legs.[3] Myoclonus seems to be generated at the sub-cortical level explaining the normal ictal EEGs.[4]

At presentation, the dystonia is usually mild-to-moderate with cervical-dystonia and writer's cramp being common.[2] Psychiatric disturbances have been reported in some families with myoclonus-dystonia.[2],[5] None of our patients showed any significant behavioral problems. Similar observations were reported previously in a French cohort.[6]

The course of myoclonus and dystonia is variable. Both worsening and spontaneous remission have been described.[2] 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.[7] 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,[3],[6] however, late-onset symptoms have been described.[7],[8]

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%.[9] 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.[9]

Myoclonus may be observed in other primary dystonias, including DYT 1 and DYT 5 dystonia.[2] Sometimes, dystonia and jerky choreic movements due to benign-hereditary-chorea may be difficult to distinguish clinically from myoclonus-dystonia.[10] A new entity called “limb dystonia with poly-mini myoclonus” has been described in a few SGCE-negative patients.[11] Other reported entities mimicking myoclonus-dystonia rarely include spinocerebellar ataxia type 14,[12] guanosine triphosphate cyclohydrolase deficiency,[13] and isolated vitamin-E-deficiency.[14]

When myoclonus and dystonia are only part of the phenotype, mitochondrial disorders, Lafora-body-disease, GM2-gangliosidosis, Niemann-Pick disease, and tyrosine hydroxylase deficiency [15] 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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Zimprich A, Grabowski M, Asmus F, Naumann M, Berg D, Bertram M, et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat Genet 2001;29:66-9.  Back to cited text no. 1
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2.
Kinugawa K, Vidailhet M, Clot F, Apartis E, Grabli D, Roze E. Myoclonus-dystonia: An update. Mov Disord 2009;24:479-89.  Back to cited text no. 2
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3.
Raymond D, Saunders-Pullman R, de Carvalho Aguiar P, Schule B, Kock N, Friedman J, et al. Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with epsilon-sarcoglycan mutations. Mov Disord 2008;23:588-92.  Back to cited text no. 3
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4.
Marelli C, Canafoglia L, Zibordi F, Ciano C, Visani E, Zorzi G, et al. A neurophysiological study of myoclonus in patients with DYT 11 myoclonus-dystonia syndrome. Mov Disord 2008;23:2041-8.  Back to cited text no. 4
    
5.
Saunders-Pullman R, Shriberg J, Heiman G, Raymond D, Wendt K, Kramer P, et al. Myoclonus dystonia: Possible association with obsessive-compulsive disorder and alcohol dependence. Neurology 2002;58:242-5.  Back to cited text no. 5
    
6.
Tezenas du Montcel S, Clot F, Vidailhet M, Roze E, Damier P, Jedynak CP, et al. Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes. J Med Genet 2006;43:394-400.  Back to cited text no. 6
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7.
Wong SH, Steiger MJ, Larner AJ, Fletcher NA. Hereditary myoclonus dystonia (DYT 11): A novel SGCE gene mutation with intrafamilial phenotypic heterogeneity. Mov Disord 2010;25:956-7.  Back to cited text no. 7
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8.
Foncke EM, Gerrits MC, van Ruissen F, Baas F, Hedrich K, Tijssen CC, et al. Distal myoclonus and late onset in a large Dutch family with myoclonus-dystonia. Neurology 2006;67:1677-80.  Back to cited text no. 8
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9.
Ritz K, Gerrits MC, Foncke EM, van Ruissen F, van der Linden C, Vergouwen MD, et al. Myoclonus-dystonia: Clinical and genetic evaluation of a large cohort. J Neurol Neurosurg Psychiatry 2009;80:653-8.  Back to cited text no. 9
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10.
Asmus F, Devlin A, Munz M, Zimprich A, Gasser T, Chinnery PF. Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. Mov Disord 2007;22:2104-9.  Back to cited text no. 10
    
11.
Asmus F, Langseth A, Doherty E, Nestor T, Munz M, Gasser T, et al. Jerky dystonia in children: Spectrum of phenotypes and genetic testing. Mov Disord 2009;24:702-9.  Back to cited text no. 11
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12.
Foncke EM, Beukers RJ, Tijssen CC, Koelman JH, Tijssen MA. Myoclonus-dystonia and spinocerebellar ataxia type 14 presenting with similar phenotypes: Trunk tremor, myoclonus, and dystonia. Parkinsonism Relat Disord 2010;16:288-9.  Back to cited text no. 12
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13.
Leuzzi V, Carducci C, Carducci C, Cardona F, Artiola C, Antonozzi I. Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome. Neurology 2002;59:1241-3.  Back to cited text no. 13
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14.
Angelini L, Erba A, Mariotti C, Gellera C, Ciano C, Nardocci N. Myoclonic dystonia as unique presentation of isolated vitamin E deficiency in a young patient. Mov Disord 2002;17:612-4.  Back to cited text no. 14
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15.
Stamelou M, Mencacci NE, Cordivari C, Batla A, Wood NW, Houlden H, et al. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 2012;79:435-41.  Back to cited text no. 15
[PUBMED]    


    Figures

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    Tables

  [Table 1]

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