Kiran Polavarapu

Reverse split hand syndrome: Dissociated intrinsic hand muscle atrophy pattern in Hirayama disease/brachial monomelic amyotrophy

Abstract Preferential involvement of C7, C8, T1 level anterior horn cells is a typical feature in Hirayama disease/brachial monomelic amyotrophy (BMMA). There are no clinico-electrophysiological studies to substantiate the peculiar pattern of muscle involvement. Thirty subjects, 10 in each group of BMMA, amyotrophic lateral sclerosis (ALS) and age-matched normal healthy subjects underwent detailed clinical and electrophysiological testing. Results showed that the mean age at evaluation for BMMA and ALS patients was 25.8 ± 3.8 and 51.8 ± 9.5 years, respectively; illness duration was 8.1 ± 5.7 years and 11.14 ± 2.85 months, respectively. Clinically, all BMMA patients had reverse of split hand (RSH) syndrome [abductor digiti minimi (ADM) affected more than abductor pollicis brevis (APB)], while 7/10 ALS patients had classical split hand syndrome (APB affected more than ADM). In BMMA, the compound muscle action potential (CMAP) of APB was preserved but reduced/absent in ADM compared to the ALS group which demonstrated reverse findings. APB/ADM ratio was >0.8 in the BMMA group (>1.4 in 80%), around 1.0 in normal controls (none had >1.4) and <0.8 in ALS (70% having values <0.6). In conclusion, RSH syndrome may provide valuable diagnostic clues to differentiate this relatively self-restricted disease from progressive degenerative disease like ALS.

Muscle MRI in Duchenne muscular dystrophy: Evidence of a distinctive pattern.

The purpose of this study was to describe the pattern of muscle involvement using MRI findings and correlate with functional as well as muscle strength measurements. Fifty genetically confirmed DMD children with a mean age of 7.6 ± 2.8 (4-15 years) underwent muscle MRI and qualitative assessment was done for muscle changes using Mercuri staging for fibro-fatty replacement on T1 sequence and Borsato score for myoedema on STIR sequence. Detailed phenotypic characterisation was done with Manual muscle testing (modified MRC grading) and Muscular Dystrophy Functional Rating Scale (MDFRS). Mercuri scoring showed severe fibro-fatty changes in Gluteus medius, minimus and Adductor magnus followed by moderate to severe changes in Gluteus maximus and Quadriceps muscles. Total sparing of Gracilis, Sartorius and Semimembranosus muscles was observed. Superficial posterior and lateral leg muscles were preferentially involved with sparing of deep posterior and anterior leg muscles. Myoedema showed significant inverse correlation with fatty infiltration in thigh muscles. Similarly, significant inverse correlation was observed between Mercuri scores and MRC grading as well as MDFRS scores. A direct linear correlation was observed between duration of illness and fibro-fatty changes in piriformis, quadriceps and superficial posterior leg muscles. There was no correlation between MRI findings and genotypic characteristics. However, this specific pattern of muscle involvement in MRI could aid in proceeding for genetic testing when clinical suspicion is high, thus reducing the need for muscle biopsy. Fibro fatty infiltration as measured by Mercuri scoring can be a useful marker for assessing the disease severity and progression.

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

Background and Purpose Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. Methods A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. Results The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. Conclusions The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

Novel TCAP mutation c.32C>A causing limb girdle muscular dystrophy 2G.

TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere, and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G.

Distal bimelic amyotrophy (DBMA): Phenotypically distinct but identical on cervical spine MR imaging with brachial monomelic amyotrophy/Hirayama disease.

Our objective was to characterize the MR imaging features in a large and distinct series of distal bimelic amyotrophy (DBMA) from India. We utilized a retrospective and prospective study on 26 cases. Results demonstrated that upper limb distal muscle wasting and weakness was predominantly symmetrical in onset. Mean age at onset was 20.9 ± 7.0 years, mean duration 83.0 ± 102.6 months. MRI carried out in 22 patients with flexion studies showed forward displacement of posterior dura in 19 (86.4%). Crescent shaped epidural enhancement on contrast was seen in 20/24 cases (83.3%), and bilateral T2W hyperintensities of cord in17 (65.4%) – symmetrical in15 cases. Maximum hyperintensity was noted at C5–C6, C6–C7 levels. Cord atrophy was noted in 24 (92.3%) cases (most affected: C5–C6, C6–C7) – symmetrical atrophy in 21cases. Cervical spine straightening occurred in six (23.1%) cases and reversal of lordosis in 15 (57.7%). In conclusion, this study confirms that DBMA is phenotypically distinct but pathophysiologically the same as brachial monomelic amyotrophy (BMMA) on MR imaging. Typical MRI features were seen in all. It is important to differentiate this disorder from ALS, which could present at a younger age as often seen among Indians. The clinical and MR imaging features are highly suggestive that DBMA, as with BMMA/Hirayama disease, occurs due to dynamic alterations at the cervical spine level.

Proximal and proximo-distal bimelic amyotrophy: Evidence of cervical flexion induced myelopathy

Abstract This report aims at describing two new clinical phenotypes associated with classical features of cervical flexion induced myelopathy (CFIM). The description is of a prospective case series of six young males presenting with progressive bilateral proximal/proximo-distal amyotrophy of upper limbs and demonstrating the typical MRI characteristics of Hirayama disease. All underwent detailed clinical, electrophysiologcal and imaging studies. The affected muscles were shoulder girdles and arms in proximal form (n = 2) and the entire upper limbs in proximo-distal form (n = 4). The mean age at onset was 21.0 ± 3.3 years, duration of illness was 6.7 ± 3.4 years, period of progression was 39.0 ± 27.3 months followed by a stable phase of 45.0 ± 50.0 months. All had severe wasting and weakness of affected muscles leading to significant disability. Nerve conduction studies revealed grossly reduced compound muscle action potential amplitudes with neurogenic pattern on electromyography of affected muscles. On MRI all revealed evidence of cervical cord atrophy with signal changes, dural detachment and extensive posterior epidural enhancement (variably from C1 to T2 level). Altered cervical curvature was prominent. In conclusion, hitherto unreported, we describe two additional clinical phenotypes (proximal and proximo-distal forms) of Hirayama disease demonstrating the cardinal imaging features of CFIM.

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK‐CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta‐analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK‐related CMS.

Ventral longitudinal intraspinal fluid collection: Rare presentation as brachial amyotrophy and intracranial hypotension

Context: Ventral longitudinal intraspinal fluid collection (VLISFC) presenting as hand amyotrophy has been described only in a few cases and there are no reports on associated intracranial CSF hypovolemia (ICH). We describe the clinical and imaging findings of a case with combined brachial amyotrophy and ICH secondary to VLISFC. Findings: A 31 year old man presented with severe positional neck discomfort, radiating pain, progressive asymmetrical wasting and weakness of distal upper limbs. Contrast Magnetic Resonance Imaging (MRI) of the spine demonstrated a ventral extradural intraspinal fluid collection extending from upper border of C6 to lower border of T3 vertebra with pockets of dorsal collection. Three-dimensional constructive interference in steady state (CISS 3D) used in spinal imaging for identification of CSF leak corroborated with the extent seen on T2 sagittal sections; however, the site of the leak was not identified. After a year he developed disturbing postural headache which was relieved in recumbent position. Follow up MRI of brain was normal while spine demonstrated significant cervical cord atrophy and bilateral cord white matter hyperintensities. Conclusion / Clinical Relevance: We report this unusual case where local compression by VLISFC located at the cervical and upper thoracic level not only caused distal bi-brachial amyotrophy mimicking Hirayama disease but also led to secondary intracranial hypotension. An early identification and intervention could possibly have prevented the onset of ICH.

Beevor's sign: a potential clinical marker for GNE myopathy.

V. Preethish-Kumar*, O. Pogoryelova*, K. Polavarapu, N. Gayathri, V. Seena, J. Hudson, I. Nishino, C. Prasad, H. Lochm€ uller** and A. Nalini** Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, India; John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru; Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India; Northern Genetics Service, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; Department of Neuromuscular Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan; and Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru, India

Natural history of a cohort of Duchenne muscular dystrophy children seen between 1998 and 2014: An observational study from South India

Background: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. There are no large studies describing its natural course from India. Materials and Methods: Immunohistochemically/genetically confirmed DMD patients diagnosed between 1998 and 2014 were ambispectively included. The main aim was to study the natural course of motor milestones, i.e., age at onset of wheelchair status, bedbound state, and age at death, which were considered as primary outcome measures. We also correlated the DMD genotype with the motor milestones and other phenotypic features. Results: A total of 500 DMD patients were included and 275 participated in the study. The mean age at symptom onset was 3.7 ± 1.9 years, mean age at presentation was 8.1 ± 2.5 years, and mean duration of illness was 4.4 ± 2.6 years. On following them over 15 years, 155 (56.4%) had attained at least one of the primary outcome measures. Wheelchair status was attained in 124 (45.1%) [mean age: 10.4 ± 1.6 years] and bedbound state in 24 (8.7%; mean age: 11.8 ± 2.2 years) patients. Seven patients (2.6%) died during the follow-up period (mean age: 15.2 ± 2.4 years). There was no significant impact of the genotypic or phenotypic features on the primary outcome. Conclusion: The pattern of major motor milestones (primary outcome measures) in this large cohort is comparable with that of the Western population despite variability in medical care. The genotypic pattern was also similar to other large studies, which suggests that DMD is a more homogeneous disorder with limited ethnic variability in its geno-phenotypic expression.