New HSP genotypes and phenotypes

Research from USA, Germany, Turkey, China, India, France, Japan, Austria

What are genotypes and phenotypes?

The distinction between genotype and phenotype is the difference between someone’s heredity, the set of genes they carry, i.e. their genotype and what that set of genes produces, i.e. their physical and other characteristics or phenotype.

Physical characteristics (phenotype) are determined by the set of genes (genotype) someone has.

Physical characteristics include appearance, development and behaviour. Examples include height; eye, skin and hair colour; body shape and size. Phenotype also includes characteristics that can be observed or measured such as levels of hormones, blood type and behaviour.

Phenotype is determined as well as by environmental influences on the genes. Identical twins, who have identical genotypes, eventually develop some differences because each twin will encounter different environmental influences as they develop and age.

5 children with sporadic SPG3A with severe, complicated HSP

Distinct phenotype/genotype correlation found in both sporadic and inherited cases related to a localized mutational cluster


Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly ‘pure’ HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants.

Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster.

Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.

SOURCE:  Hum Mol Genet. 2022 Aug 4;ddac182. doi: 10.1093/hmg/ddac182. Online ahead of print. PMID: 35925862 © The Author(s) 2022.

De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations

Julian E Alecu  1   2 Afshin Saffari  1 Catherine Jordan  1 Siddharth Srivastava  1 Craig Blackstone  3 Darius Ebrahimi-Fakhari  1   4   5   6

1. Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.

2. Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

3. Movement Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

4. Movement Disorders Program, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.

5. Intellectual and Developmental Disabilities Research Center, Boston Children’s Hospital, Boston, MA, USA.

6. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA.

MYO1H proposed as a new candidate gene for pure HSP

Common variant causing SPG33 also found but did not explain disease occurrence across the family.


In this study, we aimed to determine the genetic basis of a Turkish family related to hereditary spastic paraplegia (HSP) by exome sequencing. HSP is a progressive neurodegenerative disorder and displays genetic and clinical heterogeneity. The major symptoms are muscle weakness and spasticity, especially in the lower extremities. We studied seven affected and seven unaffected family members, as well as a clinically undetermined member, to identify the disease-causing gene. Exome sequencing was performed for four affected and two unaffected individuals.

The variants were firstly filtered for HSP-associated genes, and we found a common variant in the ZFYVE27 gene, which has been previously implied for association with HSP. Due to the incompletely penetrant segregation pattern of the ZFYVE27 variant, revealed by Sanger sequencing, with the disease in this family, filtering was re-performed according to the mode of inheritance and allelic frequencies. The resulting 14 rare variants were further evaluated in terms of their cellular functions, and three candidate variants in ATAD3C, VPS16, and MYO1H genes were selected as possible causative variants, which were analyzed for their familial segregation. ATAD3C and VPS16 variants were eliminated due to incomplete penetrance. Eventually, the MYO1H variant NM_001101421.3:c.2972_2974del (p.Glu992del, rs372231088) was found as the possible disease-causing deletion for HSP in this family.

This is the first study reporting the possible role of a MYO1H variant in HSP pathogenesis. Further studies on the cellular roles of Myo1h protein are needed to validate the causality of MYO1H gene at the onset of HSP.

SOURCE:  Mol Genet Genomics. 2022 Jul;297(4):1141-1150. doi: 10.1007/s00438-022-01910-5. Epub 2022 Jun 15. PMID: 35704118 © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

MYO1H is a novel candidate gene for autosomal dominant pure hereditary spastic paraplegia

Ece Selçuk  1   2 Koray Kırımtay  1 Benan Temizci  1   3 Şeyma Akarsu  1   3 Elif Everest  1   3 Mehmet Barış Baslo  4 Meltem Demirkıran  5 Zuhal Yapıcı  4 Arzu Karabay  6   7

1. Molecular Biology, Genetics-Biotechnology, Graduate School of Science, Engineering and Technology, Istanbul Technical University, 34469, Istanbul, Turkey.

2. Department of Molecular Biology and Genetics, Istanbul Medeniyet University, Istanbul, 34700, Turkey.

3. Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, 34469, Turkey.

4. Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093, Istanbul, Turkey.

5. Department of Neurology, Faculty of Medicine, Çukurova University, 01330, Adana, Turkey.

6. Molecular Biology, Genetics-Biotechnology, Graduate School of Science, Engineering and Technology, Istanbul Technical University, 34469, Istanbul, Turkey.

7. Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, 34469, Turkey.

3 new RTN2 variants causing SPG12 identified

Each case complicated HSP but different phenotype

Objective: Spastic paraplegia-12 (SPG12) is a subtype of hereditary spastic paraplegia caused by Reticulon-2 (RTN2) mutations. We described the clinical and genetic features of three SPG12 patients, functionally explored the potential pathogenic mechanism of RTN2 mutations, and reviewed RTN2-related cases worldwide.

Methods: The three patients were 31, 36, and 50 years old, respectively, with chronic progressive lower limb spasticity and walking difficulty. Physical examination showed elevated muscle tone, hyperreflexia and Babinski signs in the lower limbs. Patients 1 and 3 additionally had visual, urinary, and/or coordination dysfunctions. Patient 2 also had epileptic seizures. RTN2 mutations were identified by whole-exome sequencing, followed by Sanger sequencing, segregation analysis, and phenotypic re-evaluation. Functional examination of identified mutations was further explored.

Results: Three variants in RTN2 were identified in Patient 1 (c.103C>T, p.R35X), Patient 2 (c.230G>A, p.G77D), and Patient 3 (c.337C>A, p.P113T) with SPG, respectively. Western blotting revealed the p.R35X with smaller molecular weight than WT and other two missense mutants. Immunostaining showed the wild type colocalized with endoplasmic reticulum (ER) in vitro. p.R35X mutant diffusely distributes in the cytoplasm, losing colocalization with ER. p.G77D and p.P113T co-localized with ER, which was abnormally aggregated in clumps.

Interpretation: In this study, we identified three cases with complicated SPG12 due to three novel RTN2 mutations, respectively, presenting various phenotypes: classic SPG symptoms with (1) visual abnormalities and sphincter disturbances or (2) seizures. The phenotypic heterogeneity might arise from the abnormal subcellular localization of mutant Reticulon-2 and improper ER morphogenesis, revealing the RTN2-related spectrum is still expanding.

SOURCE:  Ann Clin Transl Neurol. 2022 Aug;9(8):1108-1115. doi: 10.1002/acn3.51605. Epub 2022 Jun 9. PMID: 35684947 © 2022 The Authors.

New phenotype of RTN2-related spectrum: Complicated form of spastic paraplegia-12

Wotu Tian #  1 Haoran Zheng #  1   2 Zeyu Zhu #  1 Chao Zhang  3 Xinghua Luan  1 Li Cao  1   2

1. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China.

2. School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China.

3. Suzhou Hospital of Anhui Medical University Suzhou Municipal Hospital of Anhui Province, Suzhou, 234000, China.

#. Contributed equally.

Similarities and overlap in HSP and SCA phenotypes described

Background and purpose: A variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs.

Methods: A total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses.

Results: The mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28.

Conclusion: Causative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs.

SOURCE:  Front Neurol. 2022 Apr 28;13:872927. doi: 10.3389/fneur.2022.872927. eCollection 2022.  PMID: 35572931 Copyright © 2022 Shi, Wang, Chen, Wang, Niu, Li, Li and Zhang.

Clinical Features and Genetic Spectrum of Patients with Clinically Suspected Hereditary Progressive Spastic Paraplegia

Yuzhi Shi  1 An Wang  1 Bin Chen  1 Xingao Wang  1 Songtao Niu  1 Wei Li  2   3 Shaowu Li  4 Zaiqiang Zhang  1

1. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

2. China National Clinical Research Center for Neurological Diseases, Beijing, China.

3. Monogenic Disease Research Center for Neurological Disorders & Precision Medicine Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

4. Department of Functional Neuroimaging, Beijing Neurosurgical Institute, Beijing, China.

New variant causing SPG7 found

Complicated HSP with ataxia and cognitive impairments

Background: Hereditary spastic paraplegia 7 (SPG7) is one of the subtypes of autosomal-recessive hereditary spastic paraplegia, which is a clinically heterogeneous neurodegenerative disorder. SPG7 often displays a complicated phenotype, including optic atrophy, ophthalmoparesis, and impaired emotional communication. In the Chinese population, sporadic cases of SPG7 variant-associated spastic ataxia are rarely reported.

Case presentation: We carefully analysed the clinical features, imaging and genetic tests of two sporadic patients with SPG7, both from the Hebei region of China. One patient presented with progressive bilateral lower limb weakness, spastic-ataxia and no cognitive impairment. Brain MRI revealed mild cerebellar atrophy. Genetic analysis revealed c.1150_1151insCTAC (p.G384Afs*13) frameshift variant and exon1-3 heterozygous deletion. The other patient presented with progressive bilateral lower limb weakness, ataxia, dysarthria and a mild psychosis associated with persecutory delusions, which drew almost no attention, in addition to mild cognitive impairments characterized by a decrease in verbal memory and executive function. Genetic analysis identified two heterozygous variants in the SPG7 gene: c.1150_1151insCTAC (p.G384Afs*13) and c.1496delC (p.Q500Sfs*13).

Conclusions: The c.1496delC (p.Q500Sfs*13) variant in exon 11 has not been reported before. The c.1150_1151insCTAC variant is speculated to be a hotspot variant in the Chinese population. Patients with SPG7 may have cognitive impairments and psychosis, displaying specific characteristics, which should be of concern.

SOURCE:  BMC Neurol. 2022 May 30;22(1):200. doi: 10.1186/s12883-022-02706-1. PMID: 35637455 © 2022. The Author(s).

A novel compound heterozygous SPG7 variant is associated with progressive spastic ataxia and persecutory delusions found in Chinese patients: two case reports

Shan Wang #  1 Yaye Wang #  1   2 Yue Wu  1   2 Jinru Zhang  1   2 Weilin Zhang  1 Chang Li  1 Xueqin Song  3   4

1. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.

2. Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, 050000, People’s Republic of China.

3. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.

4. Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, 050000, People’s Republic of China.

#. Contributed equally.

SPG76 phenotype described

New variant in the CAPN1 gene discovered


HSP-76 is an autosomal recessive neurological disorder.[2] It is characterized by onset of slowly progressive spasticity of the lower limbs in young adults.

We evaluated a family of 8 affected individuals hailing from Belgaum District in Karnataka State, India, in the Neurology Out-Patient Clinic of our Institute. The proband was a 30-year-old male, who was apparently normal till the age of 22 years. The first symptom he noticed was a tendency to drag his left lower limb while walking. Later, he noticed that his left lower limb would cross in front of his right while walking, resulting in slowness and change in his gait while walking. Over a period of few months, he started tripping over small obstacles. Gradually the symptoms appeared in his right lower limb, with slow progression. He developed progressive stiffness and weakness of both lower limbs with reduced range of movements at the joints.

Initially, he had no difficulty in getting up from squatting position or buckling of knees. He never had symptoms in his upper limbs and no incoordination, sensory, cognitive, or sphincter disturbances. Over a period of years, the patient gradually developed dysarthria, while his lower limb symptoms progressed for a while and subsequently plateaued. The patient was able to perform his activities of daily living on his own with difficulty and remained independent and ambulant without assistance.

Detailed family history revealed that multiple members of his family were affected. The patient was born to a consanguineous marriage, and he was the third born child. His sibling brother is affected, while his sister is not. There are also several affected members in his extended family.

Higher mental functions including language were normal. There were no cranial nerve abnormalities. He had marked dysarthria characterized by slow, strained speech with slurring of syllables. He had prominent spasticity in the lower limbs, predominantly involving the hamstrings and adductors. Upper limb spasticity was milder in degree. He had Grade 4 power in all the limbs along with exaggerated deep tendon reflexes, ankle and patellar clonus and extensor response to the plantar reflex on both sides. Sensory system examination was normal. There was no in-coordination or ataxia. Skull and spine were normal. Gait testing revealed a slow, spastic paraparetic gait with prominent scissoring, but he could walk unassisted. There were no neurocutaneous markers.

The genetic study revealed the presence of a homozygous variant (c.1148 G > A; p.Gly383Asp) in CAPN1 gene, in the index patient. This variant was previously unreported in literature. Homozygous mutation in CAPN1 gene is known to cause HSP-76,[2] and hence this mutation is the most likely pathogenic variant in this family, thus confirming the diagnosis of HSP -76.

The current study is in concordance with previous studies that rare homozygous or compound-heterozygous mutations in CAPN1 cause a complicated form of HSP.[3] Most of the affected individuals from these families suffer from additional neurological symptoms in addition to the typical spasticity of the lower limbs, such as upper-extremity hyper-reflexia, dysarthria, and gait ataxia.

These features are also seen in other autosomal-recessive forms of HSP. For example, individuals with AR-HSP caused by mutations in SPG7 often present with phenotypes very similar to those described in the current study, including symptoms such as dysarthria, ataxia, upper-extremity hyperreflexia, amyotrophy, pes cavus, and sensory neuropathy.[8],[9]

Read more …

SOURCE:  Ann Indian Acad Neurol. 2022 May-Jun;25(3):555-558. doi: 10.4103/aian.aian_977_21. Epub 2022 May 3. PMID: 35936610

A novel mutation of CAPN1 gene causing hereditary spastic Paraplegia-76

Vijayendra R Chinta  1 Pramod Krishnan  1

  1. Department of Neurology, Manipal Hospital, Bengaluru, Karnataka, India.

New variant identified in UBAP1 gene (SPG80)

Exon 4 identified as a mutational hotspot

Hereditary Spastic Paraplegia (HSP) is considered to be one of the common neurodegenerative diseases with marked genetic heterogeneity. Recently, the mutations in ubiquitin-associated protein 1 (UBAP1) have been described in patients with HSP, known as spastic paraplegias 80 (SPG80).

Here, we report a Chinese HSP family presenting a frameshift mutation in the UBAP1 gene leading to complex HSP. Their clinical features encompassed spastic paraparetic gait, exaggerated patellar tendon reflexes, bilateral Babinski signs, and hyperactive Achilles tendon reflex. The proband also had severe urinary incontinence and a dermoid cyst at the lumbar 4-5 spinal cord, which rarely occurs in HSP patients.

Following whole-exome sequencing, a novel heterozygous mutation (c.437dupG, NM_016,525) was identified in the UBAP1 that segregated with the family’s phenotype and resulted in truncating UBAP1 protein (p.Ser146ArgfsTer13). Moreover, we reviewed the genotypes of UBAP1 and the phenotypic variability in 90 HSP patients reported in the literature. We found that the age of onset in UBAP1-related patients was juvenile, and there were population differences in the age of onset.

The main complications were lower extremity spasticity, hyperreflexia, and the Babinski sign. Exon 4 of UBAP1 was identified as a mutation hotspot region. Our study expands the knowledge of UBAP1 mutations, which will aid in HSP patient counseling. Further molecular biological research is needed to explore the genotype-phenotype correlations of UBAP1-related HSP.

SOURCE:  Front Genet. 2022 Jul 14;13:936292. doi: 10.3389/fgene.2022.936292. eCollection 2022. PMID: 35928447 Copyright © 2022 Li, Huang, Chai, Zhu, Huang, Ma, Zhang and Xie.

A novel mutation in the UBAP1 gene causing hereditary spastic paraplegia: A case report and overview of the genotype-phenotype correlation

Peiqiang Li  1 Xiande Huang  2 Senmao Chai  1 Dalin Zhu  3 Huirong Huang  4 Fengdie Ma  1 Shasha Zhang  1 Xiaodong Xie  1

1. Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.

2. Department of Urology, Gansu Provincial Hospital, Lanzhou, China.

3. Medical Imaging Center, Gansu Province Maternal and Child-care Hospital, Lanzhou, China.

4. Department of Respiratory Medicine, Lanzhou University Second Hospital, Lanzhou, China.

PLP1-related disorders including SPG2 studied


Pelizaeus-Merzbacher Disease (PMD) is an inherited leukodystrophy affecting the central nervous system (CNS)-a rare disorder that especially concerns males. Its estimated prevalence is 1.45-1.9 per 100,000 individuals in the general population. Patients affected by PMD exhibit a drastic reduction or absence of myelin sheaths in the white matter areas of the CNS. The Proteolipid Protein 1 (PLP1) gene encodes a transmembrane proteolipid protein. PLP1 is the major protein of myelin, and it plays a key role in the compaction, stabilization, and maintenance of myelin sheaths. Its function is predominant in oligodendrocyte development and axonal survival. Mutations in the PLP1 gene cause the development of a wide continuum spectrum of leukopathies from the most severe form of PMD for whom patients exhibit severe CNS hypomyelination to the relatively mild late-onset type 2 spastic paraplegia, leading to the concept of PLP1-related disorders. The genetic diversity and the biochemical complexity, along with other aspects of PMD, are discussed to reveal the obstacles that hinder the development of treatments. This review aims to provide a clinical and mechanistic overview of this spectrum of rare diseases.

SOURCE:  Biomedicines. 2022 Jul 15;10(7):1709. doi: 10.3390/biomedicines10071709. PMID: 35885014

Mutation of Proteolipid Protein 1 Gene: From Severe Hypomyelinating Leukodystrophy to Inherited Spastic Paraplegia

Guy Khalaf  1 Claudia Mattern  2 Mélina Begou  3 Odile Boespflug-Tanguy  4 Charbel Massaad  5 Liliane Massaad-Massade  1

1. U1195 Diseases and Hormones of the Nervous System, INSERM and Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France.

2. M&P Pharma, Schynweg 7, 6376 Emmetten, Switzerland.

3. Neuro-Dol, CNRS, Inserm, Université Clermont Auvergne, 63000 Clermont-Ferrand, France.

4. UMR 1141, INSERM, NeuroDiderot Université Paris Cité and APH-P, Neuropédiatrie, French Reference Center for Leukodystrophies, LEUKOFRANCE, Hôpital Robert Debré, 75019 Paris, France.

5. UMRS 1124, INSERM, Université Paris Cité, 75006 Paris, France.

New variant in B4GALNT1 gene causing SPG26 found


Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings.

We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26).

Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.

SOURCE:  Am J Med Genet A. 2022 Sep;188(9):2590-2598.  doi: 10.1002/ajmg.a.62880. Epub 2022 Jul 1. PMID: 35775650 © 2022 Wiley Periodicals LLC.

Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis

Julian Emanuel Alecu  1 Yuhsuke Ohmi  2   3 Robiul H Bhuiyan  2   4 Kei-Ichiro Inamori  5 Takahiro Nitta  5 Afshin Saffari  1 Hellen Jumo  1 Marvin Ziegler  1 Claudio Melo de Gusmao  1   6 Nutan Sharma  7 Shiho Ohno  8 Noriyoshi Manabe  8 Yoshiki Yamaguchi  8 Mariko Kambe  2 Keiko Furukawa  2 Mustafa Sahin  1   9   10 Jin-Ichi Inokuchi  5   11 Koichi Furakawa  2 Darius Ebrahimi-Fakhari  1   6   10   12

1. Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2. Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Kasugai, Japan.

3. Department of Medical Technology, Chubu University College of Life and Health Sciences, Kasugai, Japan.

4. Department of Biochemistry and Molecular Biology, University of Chittagong Faculty of Biological Sciences, Chittagong, Bangladesh.

5. Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

6. Movement Disorders Program, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

7. Movement Disorders Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8. Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

9. Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

10. Intellectual and Developmental Disabilities Research Center, Boston Children’s Hospital, Boston, Massachusetts, USA.

11. Core for Medicine and Science Collaborative Research and Education (MS-CORE), Project Research Center for Fundamental Sciences, Osaka University, Osaka, Japan.

12. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, Massachusetts, USA.

New variant in ENTPD1 gene causing SPG64 discovered in 2 siblings


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.

SOURCE:  Am J Med Genet A. 2022 Sep;188(9):2712-2717.  doi: 10.1002/ajmg.a.62878. Epub 2022 Jun 27. PMID: 35758610 © 2022 Wiley Periodicals LLC.

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

Akgün Ölmez  1 Gökhan Ozan Çetin  2 Kadri Karaer  2

1. Pediatric Neurology Private Office, Denizli, Turkey.

2. Faculty Of Medicine, Department of Medical Genetics, Pamukkale University, Denizli, Turkey.

2 new variants causing SPG39 found.

Expanded spectrum of associated clinical phenotype described.

Objectives: The term hereditary spastic paraplegia comprises an ever-expanding array of neurological disorders with distinct aetiologies. Spastic paraplegia gene 39 is one of the many genetically defined types with features of other organs and neurological systems in addition to paraspasticity.

We describe a large kindred with a novel clinical phenotype as, in addition to spastic paraplegia, affected subjects suffered from a prominent cerebellar oculomotor dysfunction with two hitherto undescribed mutations of PNPLA6.

Methods: Three of five genetically tested family members of a large kindred were affected by spastic gait and a unique and prominent cerebellar oculomotor dysfunction. Further clinical, imaging, laboratory and videonystagmographic data were analyzed. Genetic analysis was done using next-generation sequencing.

Results: The most salient clinical feature, in addition to paraspasticity, in three of five subjects was cerebellar oculomotor dysfunction with an upbeating nystagmus provoked by downward gaze. Genetic analysis revealed two hitherto unknown sequence variants in the PNPLA6 gene, a splice-site variant c.1635 + 3G > T and a missense variant c.3401A > T, p.(Asp1134Val). In addition to cerebellar oculomotor dysfunction, compound-heterozygous siblings presented with paraspasticity and a moderate hypogonadotropic hypogonadism in the female. A paternal uncle being homozygous for the splice-site variant of PNPLA6 presented with increased lower limb reflexes and an unstable gait. Treatment with 4-aminopyridine, a potassium channel blocker, lead to meaningful improvement of clinical symptoms.

Conclusions: The unique and prominent cerebellar ocular motor disorder in our family broadens the spectrum of clinical phenotypes associated with variations in the PNPLA6 gene. The finding of paraspasticity with cerebellar oculomotor dysfunction alongside inconspicuous brainstem imaging may raise suspicion of complex HSP with PNPLA6 mutations.

SOURCE:  J Neurol. 2022 Aug 10.  doi: 10.1007/s00415-022-11313-6. Online ahead of print.  PMID: 35947152 © 2022. The Author(s).

Novel phenotype with prominent cerebellar oculomotor dysfunction in spastic paraplegia type 39

Sebastian Viertauer #  1 Ingo Kurth  2 Katja Eggermann  2 Christian Eggers #  3

1. Department of Neurology, Kepler University Hospital, Krankenhausstr. 9, 4020, Linz, Austria.

2. Department of Human Genetics, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.

3. Department of Neurology, Kepler University Hospital, Krankenhausstr. 9, 4020, Linz, Austria.

#. Contributed equally.

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