The Genotypic and Phenotypic Spectrum of <i>BICD2</i> Variants in Spinal Muscular Atrophy

Koboldt, Daniel C.; Waldrop, Megan A.; Wilson, Richard K.; Flanigan, Kevin M.

doi:10.1002/ana.25704

Cited by 23 publications

(35 citation statements)

References 47 publications

(96 reference statements)

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“…In contrast to the milder form (SMALED2A) mostly transmitted from an affected parent, all but one mutation in severe cases occurred de novo (in the remainder case segregation analysis was not available), confirming the association of de novo mutations with the most severe forms (Koboldt et al, 2020). Despite variants in CC2 and CC3 are more often associated with severe disease than variants in CC1 (Koboldt et al, 2020), genotype–phenotype correlations are not utterly evident and other molecular mechanisms should be investigated to elucidate such a broad phenotypic spectrum.…”

Section: Discussionmentioning

confidence: 72%

Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2‐opathy

Marchionni

Agolini

Mastromoro

et al. 2021

American J of Med Genetics Pt A

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BICD2 (BICD Cargo Adaptor 2, MIM*609797) mutations are associated with severe prenatal‐onset forms of spinal muscular atrophy, lower extremity‐predominant 2B (SMALED2B MIM 618291) or milder forms with childhood‐onset (SMALED2A MIM 615290). Etiopathogenesis is not fully clarified and a wide spectrum of phenotypic presentations is reported, ranging from extreme prenatal forms with adverse outcome, to slow progressive late‐onset forms. We report a fetus at 22 gestational weeks with evidence of Arthrogryposis Multiplex Congenita on ultrasound, presenting with fixed extended lower limbs and flexed upper limbs, bilateral clubfoot and absent fetal movements. A trio‐based prenatal Exome Sequencing was performed, disclosing a de novo heterozygous pathogenic in frame deletion (NM_015250.3: c.1636_1638delAAT; p.Asn546del) in BICD2. After pregnancy termination, quantitative analysis on NeuN immunostained spinal cord sections of the ventral horns, revealed that neuronal density was markedly reduced compared to the one of an age‐matched normal fetus and an age‐matched type‐I Spinal Muscular Atrophy sample, used as a comparative model. The present case, the first prenatally diagnosed and neuropathologically characterized, showed an early motor neuron loss in SMALED2B, providing further insight into the pathological basis of BICD2‐opathies.

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Section: Discussionmentioning

confidence: 72%

Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2‐opathy

Marchionni

Agolini

Mastromoro

et al. 2021

American J of Med Genetics Pt A

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“…A heterozygous missense mutation was found in the coding region of the BICD2 gene at c.1196G>A (p.Arg399His). Several studies have reported BICD2 gene mutations in patients with distal spinal muscular atrophy (SMA) [ 76 ].…”

Section: Resultsmentioning

confidence: 99%

“…[75] Ref. [76] Abbreviations for Table In comparison with AO-ALS, JALS had a slower disease progression, with the exception of FUS and SOD1-associated JALS. It is also interesting to note that FUS and SOD1…”

Section: Selected Referencesmentioning

confidence: 99%

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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“…This domain interacts with kinesin-1, a representative motor protein, as well as dynein. According to a recent review, Cys542 is included in one of the hotspot domains of the BICD2 variants in SMA-LED [10]. They examined the relationship between variant location and clinical features.…”

Section: Discussionmentioning

confidence: 99%

A case of severe autosomal dominant spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 mutation

Ueda

Suganuma

Narumi-Kishimoto

et al. 2021

Brain and Development

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Background: Heterozygous variants in BICD2 cause autosomal dominant spinal muscular atrophy with lower extremity predominance. These variants are also identified in individuals with severe forms of congenital muscle atrophy representing arthrogryposis multiplex. Case report: A girl was born with severe muscle weakness and respiratory distress. A fetal ultrasound had detected polyhydramnios and multiple joint contractures in utero. She was born with severe muscle weakness and respiratory distress. Bilateral hip joint dislocation and multiple bone fractures were also present at birth. Although she depends on medical care, including assisted ventilation and tube feeding, she has reached eight years of age. Her motor developmental skills were reduced owing to muscle weakness and deformity of her lower extremities, whereas her cognitive development slowly but steadily grew. Whole exome sequencing revealed a novel de novo missense BICD2 variant (c.1625G > A, p.(Cys542Tyr)), which was evaluated as likely pathogenic. Conclusion: This is the first case report of a severe form of spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 variant in Japan.

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The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy

Cited by 23 publications

References 47 publications

Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2‐opathy

Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2‐opathy

Juvenile Amyotrophic Lateral Sclerosis: A Review

A case of severe autosomal dominant spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 mutation

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