Inspired by colleagues’ patients
Wang J, Zhang Q, Chen Y, Yu S, Wu X, Bao X. Rett and
Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene. Mol
Genet Genomic Med. 2019 Nov;7(11):e968.
Abstract
BACKGROUND:
This study aimed to investigate the new genetic etiologies
of Rett syndrome (RTT) or Rett-like phenotypes.
METHODS:
Targeted next-generation sequencing (NGS) was performed on
44 Chinese patients with RTT or Rett-like phenotypes, in whom genetic analysis
of MECP2, CDKL5, and FOXG1 was negative.
RESULTS:
The detection rate was 31.8% (14/44). A de novo pathogenic
variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all
core features of typical RTT. A patient with atypical RTT was detected having
de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally,
compound heterozygous pathogenic variants of PPT1 gene were detected in a girl,
who initially displayed typical RTT features, but progressed into neuronal
ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C,
WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort.
CONCLUSIONS:
It is the first time that pathogenic variants of GRIN1 and
KIF1A were linked to RTT and Rett-like profiles. Our findings expanded the
genetic heterogeneity of Chinese RTT or Rett-like patients, and also suggest
that some patients with genetic metabolic disease such as NCL, might displayed
Rett features initially, and clinical follow-up is essential for the diagnosis.
Pennings M, Schouten MI, van Gaalen J, Meijer RPP, de Bot
ST, Kriek M, Saris CGJ, van den Berg LH, van Es MA, Zuidgeest DMH, Elting MW,
van de Kamp JM, van Spaendonck-Zwarts KY, Die-Smulders C, Brilstra EH,
Verschuuren CC, de Vries BBA, Bruijn J, Sofou K, Duijkers FA, Jaeger B, Schieving JH, van
de Warrenburg BP, Kamsteeg EJ. KIF1A variants are a frequent cause of
autosomal dominant hereditary spastic paraplegia. Eur J Hum Genet. 2020 Jan;28(1):40-49.
Abstract
Variants in the KIF1A gene can cause autosomal recessive
spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or
autosomal (de novo) dominant mental retardation type 9. More recently, variants
in KIF1A have also been described in a few cases with autosomal dominant
spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a
clinical exome sequencing cohort of 347 individuals with a mostly 'pure'
spastic paraplegia. In these patients, spastic paraplegia was slowly
progressive and mostly pure, but with a highly variable disease onset (0-57
years). Segregation analyses showed a de novo occurrence in seven cases, and a
dominant inheritance pattern in 11 families. The motor domain of KIF1A is a
hotspot for disease causing variants in autosomal dominant spastic paraplegia,
similar to mental retardation type 9 and recessive spastic paraplegia type 30.
However, unlike these allelic disorders, dominant spastic paraplegia was also
caused by loss-of-function variants outside this domain in six families. Finally,
three missense variants were outside the motor domain and need further
characterization. In conclusion, KIF1A variants are a frequent cause of
autosomal dominant spastic paraplegia in our cohort (6-7%). The identification
of KIF1A loss-of-function variants suggests haploinsufficiency as a possible
mechanism in autosomal dominant spastic paraplegia.
Van Beusichem AE, Nicolai J, Verhoeven J, Speth L, Coenen M,
Willemsen MA, Kamsteeg EJ, Stumpel C, Vermeulen RJ. Mobility
Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene.
Neuropediatrics. 2019 Dec 5. doi: 10.1055/s-0039-3400988. [Epub ahead of print]
Abstract
Several de novo variants in the KIF1A gene have been
reported to cause a complicated form of hereditary spastic paraplegia.
Additional symptoms include cognitive impairment and varying degrees of
peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We
describe four patients (ages 10-18 years), focusing on their mobility and gait
characteristics. Two patients were not able to walk without assistance and
showed a severe abnormal gait pattern, crouch gait. At examination, severe
contractures were found.In addition to describing the different phenotypes with
specific attention to gait in our cases, we reviewed known KIF1A mutations and
summarized their associated phenotypes.We conclude that mobility and cognition
are severely affected in children with spastic paraplegia due to de novo KIF1A
mutations. Deterioration in mobility is most likely due to progressive spasticity,
muscle weakness, and the secondary development of severe contractures, possibly
combined with an additional progressive polyneuropathy. Close follow-up and
treatment of these patients are warranted.
Kurihara M, Ishiura H, Bannai T, Mitsui J, Yoshimura J,
Morishita S, Hayashi T, Shimizu J, Toda T, Tsuji S. A Novel de novoKIF1A Mutation
in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, And
Spastic Paraplegia. Intern Med. 2019 Dec 6. doi:
10.2169/internalmedicine.3661-19. [Epub ahead of print]
Abstract
Heterozygous mutations in KIF1A have been reported to cause
syndromic intellectual disability or pure spastic paraplegia. However, their
genotype-phenotype correlations have not been fully elucidated. We herein
report a man with autism and hyperactivity along with sensory disturbance and
spastic paraplegia, carrying a novel de novo mutation in KIF1A (c.37C>T
[p.R13C]). Autism and hyperactivity have only previously been reported in a patient
with c.38 G>A (R13H) mutation. This case suggests that alterations in this
arginine at codon 13 might lead to a common clinical spectrum and further
expand the genetic and clinical spectra associated with KIF1A mutations.
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