Posted - February 2019 in Research Highlights
Research from China, Japan, Denmark, Czech Republic, Italy, Canada, Saudi Arabia, the UK and Portugal
SPG76 HSP can present with ataxia
3 new mutations found in CAPN1 gene
AIMS AND OBJECTIVE: To characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP).
BACKGROUND: The CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia.
METHOD: Patients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families.
RESULTS: Affected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy).
CONCLUSION: The phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family.
SOURCE: Eur J Med Genet. 2018 Dec 17. pii: S1769-7212(18)30416-6. doi: 10.1016/j.ejmg.2018.12.010. [Epub ahead of print] PMID: 30572172 Copyright © 2018. Published by Elsevier Masson SAS.
CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia.
1 Department of Medicine (Neurology), University of Alberta, Edmonton, Canada. Electronic address: [email protected]
2 Department of Human Genetics, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Montreal Neurological Institute, McGill University, Montreal, Canada.
3 Department of Medicine (Neurology), University of Alberta, Edmonton, Canada.
4 Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Montreal Neurological Institute, McGill University, Montreal, Canada.
5 Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
6 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
7 Department of Medicine (Neurology), University of Alberta, Edmonton, Canada; Departments of Medical Genetics and Pediatrics, University of Alberta, Edmonton, Canada.
First SPG7 HSP case in China
New compound heterozygous mutation identified
BACKGROUND: Autosomal recessive hereditary spastic paraplegias (ARHSPs) are a group of clinically and genetically heterogeneous neurodegenerative diseases with progressive spasticity and weakness in the lower limbs. Mutations in the Spastic Paraplegia gene 7 (SPG7) account for about 5-21% of ARHSP cases. However, in Asians, few reports about the mutations exist. In this study, we firstly report a novel finding from a Chinese family with compound heterozygous SPG7 mutations, in which three siblings were affected with a complicated form of ARHSP.
CASE PRESENTATION: A 56-year-old man presented with progressive stiffness, weakness and ataxia in the lower limbs. Two sisters of him had similar symptoms and dysarthria. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy in each of the patients. Genetic analysis, which exerted a targeted next generation sequencing (NGS) panel covering 917 comprehensive ataxia genes to the proband, followed by Sanger sequencing of candidate genes in other eight family members, was used to find the etiology of the disease. Ultimately, we identified compound heterozygous SPG7 mutations with two mutations: (c.1150_1150-1insCTAC and c.2062C > T, p.Arg688Trp) and one single nucleotide polymorphism (c.2063G > A, p.Arg688Gln).
CONCLUSIONS: The four bases insertion mutation (4bIM) was predicted to cause frameshift mutation or affect the splicing, and the last two variants were led to a stop codon mutation (p.Arg688Ter). As located in highly conserved positions and encoded paraplegin, the mutations were speculated to result in a truncated or defective protein and would be pathogenic factors of the disease.
This paper proves to be the first case report of SPG7 mutation in ARHSP reported in Chinese population. Our findings widen the spectrum of SPG7 mutations of ARHSP and indicate that the SPG7 mutation is an important cause of adult-onset undiagnosed ataxia.
SOURCE: BMC Neurol. 2018 Nov 29;18(1):196. doi: 10.1186/s12883-018-1199-9. PMID: 30497413
Identification of novel compound heterozygous SPG7 mutations-related hereditary spastic paraplegia in a Chinese family: a case report.
1 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang avenue, Wuhan, 430022, Hubei, China.
2 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang avenue, Wuhan, 430022, Hubei, China. [email protected]
3 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang avenue, Wuhan, 430022, Hubei, China. [email protected]
Very late-onset in SPG7 and SPG4 HSP studied
2 new mutations found in each type
Poor genotype-phenotype correlation observed
Hereditary spastic paraplegias (HSPs) are a diverse group of genetic conditions with variable severity and onset age. From a neurogenetic clinic, we identified 14 patients with very late-onset HSP, with symptoms starting after the age of 35. In this cohort, sequencing of known genetic causes was performed using clinically available HSP sequencing panels. We identified 4 patients with mutations in SPG7 and 3 patients with SPAST mutations, representing 50% of the cohort and indicating a very high diagnostic yield.
In the SPG7 group, we identified novel variants in two patients. We have also identified two novel mutations in the SPAST group. We present sequencing data from cDNA and RT-qPCR to support the pathogenicity of these variants, and provide observations regarding the poor genotype-phenotype correlation in these conditions that should be the subject of future study.
SOURCE: J Neurogenet. 2019 Feb 12:1-6. doi: 10.1080/01677063.2019.1566326. [Epub ahead of print] PMID: 30747022
High diagnostic yield and novel variants in very late-onset spasticity.
1 a Section of Neurology, Department of Pediatrics, University of Calgary, Calgary, Canada.
2 b Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
3 c Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Canada.
Large SPG7 study finds 7 novel mutations
Spastic ataxia common in those with British ancestry
OBJECTIVE: To clinically, genetically, and radiologically characterize a large cohort of SPG7 patients.
METHODS: We used data from next-generation sequencing panels for ataxias and hereditary spastic paraplegia to identify a characteristic phenotype that helped direct genetic testing for variations in SPG7. We analyzed MRI. We reviewed all published SPG7 mutations for correlations.
RESULTS: We identified 42 cases with biallelic SPG7 mutations, including 7 novel mutations, including a large multi-exon deletion, representing one of the largest cohorts so far described. We identified a characteristic phenotype comprising cerebellar ataxia with prominent cerebellar dysarthria, mild lower limb spasticity, and a waddling gait, predominantly from a cohort of idiopathic ataxia. We report a rare brain MRI finding of dentate nucleus hyperintensity on T2 sequences with SPG7 mutations. We confirm that the c.1529C>T allele is frequently present in patients with long-standing British ancestry. Based on the findings of the present study and existing literature, we confirm that patients with homozygous mutations involving the M41 peptidase domain of SPG7 have a younger age at onset compared to individuals with mutations elsewhere in the gene (14 years difference, p < 0.034), whereas c.1529C>T compound heterozygous mutations are associated with a younger age at onset compared to homozygous cases (5.4 years difference, p < 0.022).
CONCLUSIONS: Mutant SPG7 is common in sporadic ataxia. In patients with British ancestry, c.1529C>T allele represents the most frequent mutation. SPG7 mutations can be clinically predicted by the characteristic hybrid spastic-ataxic phenotype described above, along with T2 hyperintensity of the dentate nucleus on MRI.
SOURCE: Neurol Genet. 2018 Oct 24;4(6):e279. doi: 10.1212/NXG.0000000000000279. eCollection 2018 Dec. PMID: 30533525
Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations.
Hewamadduma CA1, Hoggard N1, O’Malley R1, Robinson MK1, Beauchamp NJ1, Segamogaite R1, Martindale J1, Rodgers T1, Rao G1, Sarrigiannis P1, Shanmugarajah P1, Zis P1, Sharrack B1, McDermott CJ1, Shaw PJ1, Hadjivassiliou M1.
1 Academic Directorate of Neurosciences (C.A.A.H., R.O’.M., M.K.R., S.P., Z.P., S.B., C.J.M., P.J.S., M.H.), Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital; Sheffield Institute for Translational Neuroscience (SITraN) (C.A.A.H., R.S., T.R., C.J.M., P.J.S., M.H.), University of Sheffield; Sheffield Diagnostic Genetics Service (N.J.B., J.M.), Sheffield Children’s NHS Foundation Trust; Department of Clinical Neurophysiology (G.R., P.S.), Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital; Academic Unit of Radiology (N.H.), University of Sheffield, Royal Hallamshire Hospital; and Sheffield NIHR Biomedical Research Centre for Translational Neuroscience (C.A.A.H., N.H., R.S., P.S., S.B., C.J.M., P.J.S., M.H.), United Kingdom.
New variant in the CPT1C gene
Nonsense mutation and benign clinical course
Hereditary spastic paraplegia 73 (SPG73) was currently identified in only one family with variant in the neuronal isoform of carnitine palmitoyl-transferase 1C (CPT1C) gene. We described a new family, in which affected individuals exhibited pure hereditary spastic paraplegia with benign clinical course.
Exome sequencing revealed a novel nonsense variant in the CPT1C gene. The level of CPT1C mutant transcript significantly decreased compared to that of wild-type transcript, and can be recovered after cycloheximide administration, which indicated that nonsense-mediated mRNA decay was a mechanism that might be responsible for the phenotype. Our findings expanded the clinical and genetic spectrum of SPG73.
SOURCE: https://onlinelibrary.wiley.com/doi/pdf/10.1002/acn3.717 doi: 10.1002/acn3.717
A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course
Daojun Hong, Lu Cong, Shanshan Zhong, Ling Liu, Yan Xu & Jun Zhang
Department of Neurology, Peking University People’s Hospital, Beijing, China
New sporadic mutation in SPG30 HSP
Caused severe complicated form of HSP
Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease.
RESULTS: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.
SOURCE: eNeurologicalSci. 2018 Nov 22;14:34-37. doi: 10.1016/j.ensci.2018.11.026. eCollection 2019 Mar. PMID: 30582020
The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case.
1 Department of Neurology, Faculty of Medicine, Kindai University, Japan.
2 Department of Life Science, Faculty of Science and Engineering, Kindai University, Japan.
3 Department of Neurology, Faculty of Medicine, The University of Tokyo, Japan.
4 Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Japan.
5 Institute of Medical Genomics, International University of Health and Welfare, Japan.
First SPG57 case in Japan
New variant identified
The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.
SOURCE: J Hum Genet. 2019 Feb;64(2):171-176. doi: 10.1038/s10038-018-0538-4. Epub 2018 Nov 22. PMID: 30467354
A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy.
1 Department of Pediatric Neurology, Miyagi Children’s Hospital, Sendai, 989-3126, Japan.
2 Department of Pediatric Orthopedic Surgery, Miyagi Children’s Hospital, Sendai, 989-3126, Japan.
3 Departments of Pediatric Neurology and Orthopedic Surgery, Takuto Rehabilitation Center for Children, Sendai, Japan.
4 Department of Neurology, Tohoku University School of Medicine, Sendai, 980-8574, Japan.
5 Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan.
6 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
7 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.
8 Department of Pediatric Neurology, Miyagi Children’s Hospital, Sendai, 989-3126, Japan. [email protected]
9 Departments of Pediatric Neurology and Orthopedic Surgery, Takuto Rehabilitation Center for Children, Sendai, Japan. [email protected]
New REEP1 variant found
Associated with peripheral neuropathy
SPG31 is a hereditary spastic paraplegia (HSP) caused by pathogenic variants in the REEP1 gene. The phenotype (SPG31) has occasionally been described with peripheral nervous system involvement, in additional to the gradually progressing lower limb spasticity that characterizes HSP.
The objective of this study was to characterize patients with pathogenic REEP1 variants and neurophysiologically assess the extent of peripheral nerve involvement in this patient group. Thirty-eight index cases were molecular-genetically tested, yielding two previously reported pathogenic REEP1 variants and a novel missense variant, in a total of four index patients. Three of four probands and five additional family members underwent nerve conduction studies, electromyography, quantitative sensory testing, and examination of the autonomic nervous system. None of the examined patients had completely unremarkable results of peripheral nerve studies. Most showed electrophysiological signs of carpal tunnel syndrome, and one patient demonstrated a multifocal compression neuropathy. Autonomic testing revealed no severe dysfunction, and findings were limited to adrenergic function.
HSP caused by pathogenic REEP1 variants may be accompanied by a generally mild and subclinical polyneuropathy with a predisposition to compression neuropathy, and should be considered in such cases.
SOURCE: J Neurol. 2019 Mar;266(3):735-744. doi: 10.1007/s00415-019-09196-1. Epub 2019 Jan 12. PMID: 30637453
Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.
1 Department of Neurology, Rigshospitalet, Neuromuscular Research Center, University of Copenhagen, Copenhagen, Denmark. [email protected]
2 Department of Clinical Neurophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
3 Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
4 Department of Neurology, Neurogenetics Clinic, Rigshospitalet, Danish Dementia Research Centre, University of Copenhagen, Copenhagen, Denmark.
5 Department of Neurology, Rigshospitalet, Neuromuscular Research Center, University of Copenhagen, Copenhagen, Denmark.
6 Department of Neurology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
New FA2H mutation identified
Associated with complicated SPG35 HSP
Biallelic pathogenic variants in FA2H gene have been repeatedly described as a cause of hereditary spastic paraplegia (HSP) type35 (SPG35). Targeted massive parallel sequencing (MPS) of the HSP genes panel revealed a novel homozygous variant c.130C > T (p.P44S) in the FA2H gene in the 30-year-old patient presenting with spastic paraplegia. The patient originated form the Czech minority in Romania. The patient manifests typical clinical signs for SPG35 (youth onset gait impairment, progressive spastic paraparesis on lower limbs, dysarthria, white matter changes in MRI).
SOURCE: J Clin Neurosci. 2019 Jan;59:337-339. doi: 10.1016/j.jocn.2018.10.094. Epub 2018 Nov 13. PMID: 30446360 Copyright © 2018 Elsevier Ltd. All rights reserved.
Autosomal recessive hereditary spastic paraplegia type SPG35 due to a novel variant in the FA2H gene in a Czech patient.
1 DNA Laboratory, Department of Paediatric Neurology, Charles University Second School of Medicine and University Hospital Motol, Prague, Czech Republic. Electronic address: [email protected]
2 DNA Laboratory, Department of Paediatric Neurology, Charles University Second School of Medicine and University Hospital Motol, Prague, Czech Republic.
3 Department of Neurology, Charles University Second School of Medicine and University Hospital Motol, Prague, Czech Republic.
4 Department of Medical Genetics, Masaryk Hospital, Ústí nad Labem, Czech Republic.
5 Centre for Medical Genetics and Reproductive Medicine GENNET, Prague, Czech Republic.
6 DNA Laboratory, Department of Paediatric Neurology, Charles University Second School of Medicine and University Hospital Motol, Prague, Czech Republic; Centre for Medical Genetics and Reproductive Medicine GENNET, Prague, Czech Republic.
New mutation found in ZFYVE26 gene
Associated with SPG15 HSP
Hereditary spastic paraplegias are clinically and genetically heterogeneous degenerative disorders, and pathological variants in the autosomal recessive ZFYVE26 gene are considered as very rare causes.
We describe a novel mutation in ZFYVE26 gene found in a patient with autosomal recessive spastic paraplegias. The use of a ‘target-gene’ approach allowed us to expand the clinical spectrum associated with hereditary spastic paraplegias.
SOURCE: J Genet. 2018 Dec;97(5):1469-1472. PMID: 30555096
Novel c.C2254T (p.Q752*) mutation in ZFYVE26 (SPG15) gene in a patient with hereditary spastic paraparesis.
1 Oasi Research Institute-IRCCS, Troina 94018, Italy. [email protected]
Brain iron accumulation not prominent in SPG35
Previously thought to be so
Mutations in the fatty-acid 2-hydroxylase (FA2H) gene cause an autosomal recessive spastic paraplegia (SPG35), often associating with cerebellar ataxia; cerebral MRI may show iron accumulation in the basal ganglia, leading to the inclusion of SPG35 among the causes of neurodegeneration with brain iron accumulation. This finding was initially considered strongly relevant for diagnosis, although its frequency is not yet established.
We found 5 novel patients (from two families) with mutations in the FA2H gene: none of them showed cerebral iron accumulation (T2-weighted images performed in all; T2 gradient-echo in 2); notably, in 1 case, iron accumulation was absent even after 18 years from disease onset on both T2 gradient-echo and susceptibility-weight MRI sequences.
Cerebral iron accumulation is not a prominent feature in SPG35 and is not always dependent on disease duration; its absence should not discourage from evoking this diagnosis.
SOURCE: Mov Disord Clin Pract. 2015 Feb 18;2(1):56-60. doi: 10.1002/mdc3.12118. eCollection 2015 Mar. PMID: 30713878
Cerebral Iron Accumulation Is Not a Major Feature of FA2H/SPG35.
1 Department of Neurology University Hospital Gui de Chauliac Montpellier France.
2 Division of Pediatric Neurology Department of Pediatrics College of Medicine King Saud University Riyadh Saudi Arabia.
3 Department of Medical Genetics University Hospital “Timone Enfants” Marseille France.
4 Institute of Genetics and Cellular and Molecular Biology INSERM U964 CNRS UMR7104 University of Strasbourg Illkirch France.
5 Department of Neurology Strasbourg University Hospital Strasbourg France.
6 Department of Neuroradiology University Hospital Gui de Chauliac Montpellier France.
7 Department of Radiology King Khalid University Hospital and College of Medicine King Saud University Riyadh Saudi Arabia.
8 University Institute of Clinical Research INSERM UMR_S 827 and Laboratoire de Genetique Moleculaire University Hospital Montpellier France.
Third case of SPG64 found
Novel missense mutation identified
Spastic paraplegia type 64 (SPG64; OMIM 615683) is a complicated form of hereditary spastic paraplegia (HSP) recently identified in individuals diagnosed with suspected neurodegenerative disease. Affected patients carry homozygous mutations in the ectonucleoside triphosphate diphosphohydrolase 1 gene (ENTPD1). Although they share common characteristics, affected individuals show slight discrepancies in some clinical aspects. At present, only two different cases of SPG64 have been diagnosed. More findings of genetic variation would be helpful to better understand the effect of mutations in the ENTPD1 gene on the neurological condition of affected individuals.
In this study, we examined a family with an individual diagnosed with suspected HSP based on clinical findings. DNA samples from the proband, her affected sister, and both parents were analyzed using next-generation sequencing. We used an in-house automated pipeline to detect potential neuromuscular disease-causing variants. Variants were confirmed by Sanger sequencing. After cosegregation analysis, the variant NM_001776.5:c.401T>G (p.M134R) of the ENTPD1 gene was identified as a novel missense mutation linked to the phenotype of SPG64 in the proband and her sister, who showed similar and distinct clinical features compared with the two cases previously described in the literature.
SOURCE: Hum Genome Var. 2019 Jan 11;6:5. doi: 10.1038/s41439-018-0036-4. eCollection 2019. PMID: 30652007
A new case of spastic paraplegia type 64 due to a missense mutation in the ENTPD1 gene.
1 1Department of Neurology, Dr.-Georges-L.-Dumont University Hospital Center, 330, University Avenue Moncton, Moncton, NB E1C 2Z3 Canada.
2 Centre de Formation Médicale du Nouveau-Brunswick, 100 Des Aboiteaux Street, Moncton, NB E1A 7R1 Canada.
3 Molecular Genetics, Dr.-Alfred-Bastarache Laboratory, 37 Providence Street, Moncton, NB E1C 8X3 Canada.
Novel variant of the KIF5A gene found
Slowly progressive phenotype resembling ALS, HSP and axonal neuropathy
KIF5A encodes the heavy chain A of kinesin; A motor protein involved in motility functions within neuron. Mutations in the KIF5A N-terminal motor domain are known to cause SPG10, an autosomal dominant hereditary spastic paraplegia (HSP), as well as rare Charcot-Marie-Tooth disease 2 (CMT2) cases. Recently C-terminal cargo-binding tail domain mutations have been associated with an amyotrophic lateral sclerosis (ALS) phenotype.
Here we describe a subject presenting with an atypical slowly progressive motor syndrome evolving over a period of 4 years; Characterized by walking difficulties; Muscle hypotrophy mainly involving upper limbs and pyramidal signs confined to the lower limbs. Electromyography demonstrated chronic neurogenic damage and active denervation while electroneurography showed slowly worsening axonal damage. We identified the novel heterozygote variant c.2341A>G in the exon 21 of the KIF5A gene resulting in the amino acid change p.Lys781Glu. The residue Lys781 is located within the terminal region of the stalk domain and is highly evolutionary conserved.
Our findings confirm that mutations in KIF5A cause ALS-like phenotypes. However, the stalk domain mutation described here appears to result in an “intermediate” slowly progressive phenotype having aspects resembling ALS as well as HSP and axonal neuropathy. We suggest that KIF5A gene should be considered as a candidate gene in all atypical progressive motor syndromes.
SOURCE: J Clin Med. 2018 Dec 22;8(1). pii: E17. doi: 10.3390/jcm8010017. PMID: 30583522
A Novel Mutation in the Stalk Domain of KIF5A Causes a Slowly Progressive Atypical Motor Syndrome.
1 Center for Neuromuscular Diseases, Unit of Neurology, ASST Spedali Civili and University of Brescia, 25100 Brescia, Italy. [email protected]
2 Center for Neuromuscular Diseases, Unit of Neurology, ASST Spedali Civili and University of Brescia, 25100 Brescia, Italy. [email protected]
3 Genomic and Post-Genomic Center, IRCCS Mondino Fundation, 27100 Pavia, Italy. [email protected]
4 Center for Neuromuscular Diseases, Unit of Neurology, ASST Spedali Civili and University of Brescia, 25100 Brescia, Italy. [email protected]
5 Genomic and Post-Genomic Center, IRCCS Mondino Fundation, 27100 Pavia, Italy. [email protected]
6 Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy. [email protected]
7 Clinical Chemistry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, 25100 Brescia, Italy. [email protected]
8 Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy. [email protected]
9 Clinical Chemistry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, 25100 Brescia, Italy. [email protected]
10 Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy. [email protected]
11 Clinical Chemistry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, 25100 Brescia, Italy. [email protected]
12 Genomic and Post-Genomic Center, IRCCS Mondino Fundation, 27100 Pavia, Italy. [email protected]
13 Center for Neuromuscular Diseases, Unit of Neurology, ASST Spedali Civili and University of Brescia, 25100 Brescia, Italy. [email protected]
New SPG52 phenotype described
Infantile-onset complicated form of HSP
Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurodegenerative disorders that result from primary retrograde dysfunction of the long descending fibers of the corticospinal tract, causing lower limb spasticity and muscular weakness. This group of diseases has a heterogeneous clinical presentation. An extensive list of associated genes, different inheritance patterns, and ages at onset have been reported in HSPs.1 Spastic paraplegia type 52 (SPG52) is an autosomal recessive disease caused by AP4S1 mutations. The disease is characterized by neonatal hypotonia that progresses to hypertonia and spasticity in early childhood, developmental delay, mental retardation, and poor or absent speech. Febrile or afebrile seizures may also occur.2,
Clinical case presentation
We report the case of a Portuguese 2-year-old boy born to healthy nonconsanguineous parents after a full-term gestation with intrauterine growth restriction after week 37. During the first months of life, the patient presented poor weight gain, hyperammonemia with elevation of glutamine and ornithine, low citrulline, and negative orotic acid. Weight recovery and normalization of amino acid profile were observed after protein restriction and remained normal after reintroduction of normal diet. Genetic study of urea cycle disorders (NAGS, CPS, and OTC) was negative. Around 9 months of age, global developmental delay, hypotonia, and strabismus were evident. Brain MRI with spectroscopy (performed at 10 months) showed delayed myelination/hypomyelination associated with a posterior perisylvian polymicrogyria, thinning of the corpus callosum, dilation and dysmorphia of the ventricles, and enlargement of the subarachnoid frontotemporal space (figure A). Spectroscopy suggested a possible discrete reduction of N-acetylaspartate. EEG showed a slight intermittent lentification in the left temporal region. At 15 months of age, the patient had 1 afebrile episode of status epilepticus. Two previous shorter episodes with fever had also occurred. Levetiracetam was started. No regression of psychomotor development after seizure was observed, and the patient has been evolving gradually with improvement of axial hypotonia. He says a few simple words, responds to his name, and has some nonverbal communication. The most recent neurologic evaluation revealed an alteration of the muscle tone (hypertonia) in the left lower limb and pyramidal signs in both legs.
Exome sequencing of the proband and parents was performed as described in Supplementary Material (links.lww.com/NXG/A86) and revealed the homozygous AP4S1 splice site NM_001128126.2:c.294+1G>T r.619_687del variant in the proband, present in the heterozygous state in the parents (figure B). The variant was located in a 2.4-Mb homozygous region of chromosome 14. This variant is extremely rare in the population, with only 1 heterozygous individual present in the Genome Aggregation Database. In silico analysis predicted the loss of the donor splice site of exon 4. A transcript size analysis and Sanger sequencing of cDNA confirmed the presence of a shorter transcript skipping exon 4 associated with the variant (figure C). As a consequence, the polypeptide of 23 amino acids (76 a.a.–98 a.a.) encoded by exon 4 is lost (figure D).
AP4S1 encodes the small subunit of the adaptor protein complex-4 (AP4 complex). This complex is recruited to the trans-Golgi network, where it mediates vesicle trafficking to endosomes or basolateral plasma membrane in a clathrin-independent manner.5 Mutations in the 4 subunits of the complex have been associated with similar autosomal recessive phenotypes mainly characterized by spastic tetraplegia.6The mutation found in our patient leads to the loss of exon 4, with predicted important consequences to the protein structure and the AP4 complex function. Anatomical changes similar to those observed in patients have been reported in an AP-4 complex knockout mouse model: enlargement of the lateral ventricles and thinning of the corpus callosum.7 Similar changes have also been seen in the patient described here, together with febrile and afebrile seizures. When exome sequencing was performed and analyzed, the patient did not show hypertonia in the lower limbs. However, as reported in other patients, this clinical entity may progress from hypotonic to hypertonic status. The most recent neurologic evaluation revealed the presence of hypertonia in the left leg, associated with pyramidal signs, suggesting the possibility of future development of a spastic paraparesis, typical of this disease.
Here, we report a case of SPG52 associated with posterior perisylvian polymicrogyria, unexplained transitory hyperammonemia, and absence of facial dysmorphisms, which suggest an expansion of the disease phenotype.
AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.