Genotype–phenotype correlation in seven motor neuron disease families with novel <scp><i>ALS2</i></scp> mutations

Sprute, Rosanne; Jergas, Hannah; Ölmez, Akgün; Alawbathani, Salem; Karasoy, Hatice; Dafsari, Hormos Salimi; Becker, Kerstin; Daimagüler, Hülya‐Sevcan; Nürnberg, Peter; Muntoni, Francesco; Topaloǧlu, Haluk; Uyanık, Gökhan; Çırak, Sebahattin

doi:10.1002/ajmg.a.61951

Cited by 19 publications

(31 citation statements)

References 44 publications

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“…In ALS2-JALS, motor neuron degeneration occurs early and generally progresses slowly [ 38 ]. A review of 21 cases in the literature showed that the average age of onset is 4.9 years, with a range of 1–20 years [ 39 ]. Clinically, there is an early development of UMN signs of spasticity, dysarthria, dysphagia, and facial weakness.…”

Section: Resultsmentioning

confidence: 99%

“…Dysarthria can proceed to anarthria within the first decade of life. Pseudobulbar affect has been noted in several large family cohorts, though cognitive decline is not a prominent feature [ 35 , 39 ]. One case report from Turkey had early onset of spasticity at age 22 months, followed by distal weakness.…”

Section: Resultsmentioning

confidence: 99%

“…ALS2-JALS patients may also develop scoliosis in their second decade [ 38 ]. Brain MRI findings are associated with mild cortical atrophy and thinning of the corticospinal tracts [ 38 , 39 ]. One report of a nerve biopsy and muscle biopsy stated that the findings are typical of a lower motor neuron disorder [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to JALS, ALS2 is associated with a spectrum of disorders, including juvenile primary lateral sclerosis [ 40 ], infantile ascending hereditary spastic paraplegia [ 35 ], and dystonia [ 41 ]. A review of ALS2 cases in 2020 [ 39 ] identified 82 cases of ALS2 , with 53 cases (64.6%) of hereditary spastic paraparesis, 25 cases of JALS (30.5%), and four cases (4.9%) of Juvenile Primary Lateral Sclerosis (JPLS). Despite the distinct clinical entities, there have not been any specified gene mutations that differentiate these disorders or the disease severity [ 39 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

“…Spatacsin may function in the maintenance of cytoskeleton stability and regulation of synaptic vesicle transport. The age of onset for SPG11-JALS ranges from 7 to 23 years, with onset most commonly in the second decade and a disease duration of 34.3 years (range of [27][28][29][30][31][32][33][34][35][36][37][38][39][40]. The clinical presentation begins with distal LMN upper or lower extremity weakness combined with UMN signs.…”

Section: Spatacsin (Spg11)mentioning

confidence: 99%

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Juvenile Amyotrophic Lateral Sclerosis: A Review

Lehky

2021

Genes

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Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases. JALS is defined as onset before age 25. We conducted a literature review of JALS and gene mutations associated with JALS. Results of the literature review show that the most common gene mutations associated with JALS are FUS, SETX, and ALS2. In familial cases, the gene mutations are mostly inherited in an autosomal recessive pattern and mutations in SETX are inherited in an autosomal dominant fashion. Disease prognosis varies from rapidly progressive to an indolent course. Distinct clinical features may emerge with specific gene mutations in addition to the clinical finding of combined upper and lower motor neuron degeneration. In conclusion, patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations. Hereditary patterns and coexisting features may be useful in determining prognosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Spatacsin (Spg11)mentioning

confidence: 99%

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Juvenile Amyotrophic Lateral Sclerosis: A Review

Lehky

2021

Genes

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PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy

Dafsari

Pemberton

Ferrer

et al. 2022

Ann Clin Transl Neurol

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Objective: Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4-phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4-kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi-allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism. Methods: Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epilepticdyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays. Results: This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants

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Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias

Ölmez¹,

Çetin

Karaer

2022

American J of Med Genetics Pt A

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Hereditary spastic paraplegias (HSP) are a group of inherited, neurodegenerative disorders characterized by progressive gait impairment, lower extremity spasticity and increased patellar reflexes. More than 80 types of HSP have been defined to date. In complicated forms, lower limb spasticity and gait impairment is accompanied by an additional neurological finding. Autosomal recessive (AR) HSPs are usually identified in complicated forms and occur more frequently in countries where consanguineous marriage is more widespread. Next generation sequencing techniques, developed in the last decade, have led to the identification of many new types of HSP and reduced the “diagnostic odyssey.” Whole exome sequencing (WES) can diagnose up to 75% of undiagnosed HSP patients. Targeted genetic analysis with good clinical phenotyping gives the best diagnostic yields for rare diseases. Clinical heterogeneity is prominent in AR complicated HSP. However, some clinical features complicating the disease or magnetic resonance imaging findings, including thin corpus callosum or white matter abnormalities, can help to distinguish some types. AR spastic paraplegia type 64 (SPG64) is a very rare HSP, caused by a mutation in the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) gene, first described in 2014. To date only nine patients from five families have been reported. We present two siblings with a novel pathogenic variant in ENTPD1, diagnosed by WES, as the sixth published family. We propose that early onset in childhood, cognitive impairment, dysarthria/anarthria, dystonia and areflexia may be the distinctive features of SPG64 and more clinical evidence from families with pathogenic ENTPD1 variants is warranted.

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Genotype–phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Cited by 19 publications

References 44 publications

Juvenile Amyotrophic Lateral Sclerosis: A Review

Juvenile Amyotrophic Lateral Sclerosis: A Review

PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy

Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias

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