Rigid Spine Syndrome among Children in Oman

Koul, Roshan; Sankhla, Dilip; Al-Jahdhami, Suad; Mani, Renjith; Rahim, Rana A.; Al-Yaarubi, Saif; Al-Kindy, Hussein; Al‐Thihli, Khalid; Al‐Futaisi, Amna

doi:10.18295/squmj.2015.15.03.010

Cited by 2 publications

(2 citation statements)

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“…The causes vary from those of bone, neuromuscular and brain diseases. It presents from the 4 th to 6 th decade of life in adults (12)(13)(14) and the first decade of life in children (15,16). Several names are given to the stiff spine in adults like axial myopathy, camptocormia and recently para spinal neuromuscular syndrome (13,14).…”

Section: Discussionmentioning

confidence: 99%

Rigid Spine Syndrome in Children

Koul

2016

Arch Neurosci

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Context: Rigid spine syndrome is rare in children. It is commonly observed in the end stage of the muscular dystrophies. Another entity called primary rigid spine or spinal muscular dystrophy syndrome, rigidity of spine is noted at the beginning of a muscle disease. The two conditions should be differentiated. Evidence Acquisition: The first child with primary rigid spine syndrome was observed in 1996. Twelve children were observed over the last eighteen years and were followed up regularly in the hospital under study. The children were diagnosed with rigid spine syndrome if there was restriction of the neck movements, particularly on the bending of the spine. The diagnosis was based on clinical features, biochemical tests, electrophysiological findings, imaging and muscle biopsy. Genetic tests were not available in the past, but were done recently in three children. Results: Twelve children (nine males and three females) were observed. Ten children had primary rigid spine and two had secondary rigid spine syndrome. Conclusions: The current study described twelve children with rigid spine syndrome from Oman; ten with primary rigid spine (rigid spinal muscular dystrophy) and two with secondary rigid spine syndrome. The condition is rare in children. Early neck stiffness is the key to diagnosis.

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Section: Discussionmentioning

confidence: 99%

Rigid Spine Syndrome in Children

Koul

2016

Arch Neurosci

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“…11 However, the genetic cause in some patients remains unknown despite screening known disease-associated genes. 13 This suggests that additional genes are yet to be associated with rigid spine syndrome.…”

Section: Introductionmentioning

confidence: 99%

Biallelic variants inHMGCS1are a novel cause of rare rigid spine syndrome

Dofash,

Miles,

Saito

et al. 2023

Preprint

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Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants inSELENONaccount for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained.In this study, we used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis. In five patients from four unrelated families, we identified biallelic variants inHMGCS1(3-hydroxy-3-methylglutaryl-coenzyme A synthase). These included six missense variants and one frameshift variant distributed throughoutHMGCS1. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some patients; one patient died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.HMGCS1encodes a key enzyme of the mevalonate pathway, disturbance of which is also associated withHMGCR-limb girdle muscular dystrophy andGGPS1-muscular dystrophy. Quantitative PCR and western blotting confirmed HMGCS1 abundance in skeletal muscle and myogenic precursors. HMGCS1 levels in skeletal muscle were comparable between healthy controls and the index case with a homozygous p.(S447P) substitution. Muscle RNA-seq for a patient with a frameshift variant (c.344_345del:p.S115Wfs*12) and an in trans substitution (p.(Q29L)) showedHMGCS1transcript levels reduced to 53% compared to controls. The substitution appeared homozygous on RNA-seq, suggesting the allele harbouring the frameshift variant undergoes nonsense mediated decay.hmgcs1-/-zebrafish displayed severe early defects, including immobility at 2 days and death by days 3 post-fertilisation. We anticipate that the variants observed in this cohort have subtle effects on HMGCS1 function given most patients survived to adulthood. In support of the variants being hypomorphic, analyses of recombinant human HMGCS1 protein and four mutants (p.S447P, p.Q29L, p.M70T, p.C268S) showed all mutants maintained their secondary structure and dimerized state and had enzymatic activity comparable to the wildtype. Thermal stability of the mutants was similar or slightly reduced compared to the wildtype. Altogether, our analyses suggest that the identified missense variants in HMGCS1 act through a hypomorphic mechanism yet to be elucidated.Here, we report an additional component of the mevalonate pathway associated with myopathy and suggest biallelic variants inHMGCS1should be considered in patients presenting with an unresolved rigid spine phenotype.

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Rigid Spine Syndrome among Children in Oman

Cited by 2 publications

References 13 publications

Rigid Spine Syndrome in Children

Rigid Spine Syndrome in Children

Biallelic variants inHMGCS1are a novel cause of rare rigid spine syndrome

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