Expanding the disease phenotype of ADSSL1-associated myopathy in non-Korean patients

Mroczek, Magdalena; Durmuş, Hacer; Bijarnia-Mahay, Sunita; Töpf, Ana; Ghaoui, Roula; Bryen, Samantha J; Duff, Jennifer; England, Eleina; Cooper, Sandra T.; MacArthur, Daniel G.; Straub, V.

doi:10.1016/j.nmd.2020.02.006

Cited by 11 publications

(14 citation statements)

References 7 publications

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“…The patient had symptom onset in his 50s of mild distal myopathy predominantly involving the posterior thigh and calf muscles (figure 3). This is in contrast to a severe childhood-onset presentation in patient (S.3) with consanguineous parents (second cousins, once removed) found to have the same mutation in homozygous state and in previously reported patients with juvenile-onset disease with homozygosity 20 and compound heterozygosity. 21 WES analysis of both parents for patient S.2 identified the mutation in his mother, suggesting germline transmission of the carrier status.…”

Section: Searching For a Second Mutationcontrasting

confidence: 90%

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

Sarkar

Owen

et al. 2021

J Neurol Neurosurg Psychiatry

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BackgroundWe used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.MethodsWES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays.ResultsMolecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients.ConclusionsIntegrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.

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Section: Searching For a Second Mutationcontrasting

confidence: 90%

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

Sarkar

Owen

et al. 2021

J Neurol Neurosurg Psychiatry

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“…Adenylosuccinate synthase-like 1 (ADSSL1) myopathy is a recently discovered ultra-rare, myopathic disease caused by a variant in ADSSL1. [1][2][3][4][5][6] ADSSL1 myopathy can vary in terms of symptom (i.e., muscle weakness, fatigue, or dysphagia) onset or muscles involved (i.e., distal, proximal, or both). [6][7][8] The pathogenesis of ADSSL1 myopathy remains incompletely understood, yet alterations in ASDDL1-based enzymatic processes have been attributed to disrupted myocyte viability and myoblast proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5][6] ADSSL1 myopathy can vary in terms of symptom (i.e., muscle weakness, fatigue, or dysphagia) onset or muscles involved (i.e., distal, proximal, or both). [6][7][8] The pathogenesis of ADSSL1 myopathy remains incompletely understood, yet alterations in ASDDL1-based enzymatic processes have been attributed to disrupted myocyte viability and myoblast proliferation. 1,3,9,10 Metabolic alterations in glycolysis and gluconeogenesis, along with ATP production are also implicated.…”

Section: Introductionmentioning

confidence: 99%

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A pilot investigation of muscle integrity in patients with ADSSL1 myopathy using electrical impedance myography

Farid,

Golden,

et al. 2023

Muscle and Nerve

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Introduction/AimsADSSL1 myopathy (OMIM 617030) is a recently discovered, congenital myopathic disease caused by a pathogenic variant in ADSSL1. ADSSL1 is an enzyme involved in the purine nucleotide process and facilitates the conversion of inosine monophosphate to adenosine monophosphate within myocytes. Electrical impedance myography (EIM) is a portable, non‐invasive, and cost‐effective method for characterizing muscle integrity. Three ADSSL1 patients are presented in whom characterization of muscle integrity using EIM was performed.MethodsA 15‐y‐old male, 20‐y‐old female, and 63‐y‐old male each with a pathogenic variant in ADSSL1 [c.901G > A] as well as three, age‐gender matched healthy controls (HCs) were enrolled. Study participants were phenotyped using a virtual EIM procedure.ResultsADSSL1 myopathy patients presented with variable onset of physical disability, disease progression, and severity of muscle weakness. Across multiple proximal and distal muscles groups and relative to HCs, ADSSL1 myopathy patients demonstrated lower phase and reactance values, while resistance was higher, which together indicated diseased muscle.DiscussionEIM can provide a novel, non‐invasive and objective biomarker to evaluate muscle integrity in patients with ADSSL1 myopathy. Combining EIM with musculoskeletal imaging and histologic assessments in follow‐up studies may further inform on the pathophysiology of ADSSL1 myopathy.

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“…The clinical presentation of ADSSL1 myopathy includes slow running since early childhood with predominant leg involvement from adolescence and frequently diffuse muscle weakness before the occurrence of distal leg weakness [3][4][5] . Facial muscle weakness often appears by the age of 40 [1 , 3-5] .…”

Section: Introductionmentioning

confidence: 99%

An autopsied case of ADSSL1 myopathy

Motoda

Watanabe

Tachiyama

et al. 2021

Neuromuscular Disorders

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Expanding the disease phenotype of ADSSL1-associated myopathy in non-Korean patients

Cited by 11 publications

References 7 publications

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

A pilot investigation of muscle integrity in patients with ADSSL1 myopathy using electrical impedance myography

An autopsied case of ADSSL1 myopathy

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