home : about us : ahead of print : current issue : archives search instructions : subscriptionLogin 
Users online: 476      Small font sizeDefault font sizeIncrease font size Print this page Email this page

Previous Article  Table of Contents  Next Article  
Ahead of print publication

Hereditary Spastic Paraplegia Type 26 with a Novel Mutation in B4GALNT1 Gene and Literature Review of the Clinical Features

1 Department of Pediatric Neurology, Adana, Turkey
2 Department of Medical Genetics, Faculty of Medicine, Cukurova University, Adana, Turkey

Date of Submission12-Apr-2021
Date of Decision12-Jul-2021
Date of Acceptance24-Jul-2021
Date of Web Publication30-Jan-2023

Correspondence Address:
Faruk Incecık,
Department of Pediatric Neurology, Faculty of Medicine, Cukurova University, Toros mah., Barış Manço Bul. 78178 sok., Yeşilpark evleri, kat: 7, no: 13, Çukurova, Adana
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_83_21


How to cite this URL:
Incecık F, Herguner OM, Bozdogan ST. Hereditary Spastic Paraplegia Type 26 with a Novel Mutation in B4GALNT1 Gene and Literature Review of the Clinical Features. J Pediatr Neurosci [Epub ahead of print] [cited 2023 May 30]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=368817

Dear Editor,

Hereditary spastic paraplegia (HSP) is a syndromic designation for a clinically and genetically heterogeneous group of inherited neurodegenerative or neurodevelopmental disorders in which the main neurological symptoms and signs are lower limb spasticity and weakness. The estimated prevalence is 3–10 cases per 100,000 population in Europe.[1] Inheritance may be autosomal dominant, autosomal recessive, or rarely X-linked.[2] Autosomal recessive HSPs are more frequent in consanguineous populations. Autosomal recessive spastic paraplegia type 26 (SPG26) is a rare, characterized by the onset in childhood/adolescence of progressive spastic paraplegia associated mainly with cognitive impairment and developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy.[3],[4],[5] The recessively inherited SPG26 is caused by mutations in B4GALNT1, encoding the β-1-4-N-acetyl-galactosaminyl transferase which functions in the biosynthesis of complex glycosphingolipids.[6]

In the literature, a few cases have been reported with SPG26.[3],[4],[5] Here, we report SPG26 cases of Turkish origin with a novel homozygous mutation in B4GALNT1gene, presented with progressive gait disturbance, and cognitive impairment.

Case 1: A 17-year-old girl was admitted to our hospital because of progressive difficulty in walking, unsteady gait, and cognitive impairment. The parents were consanguineous. She was born at term and had no neonatal problems. She walked alone at 2.5 years old and was clumsy. At 12 years old her gait further deteriorated. Pedigree is shown in [Figure 1]. Neurological examination revealed moderate cognitive impairment, and spasticity. The deep tendon reflexes were increased in lower limbs, with bilateral Babinsky signs. She had dysarthria, dysmetria, mild bilateral foot drop, pes cavus deformities with spastic and steppage gait. Ophthalmologic examination and the other physical examination were normal. The Wechsler Intelligence Scale for Children-Revised (WISC-R) test was performed and the IQ score was 50. Laboratory investigations (metabolic and biochemical tests), brain magnetic resonance imaging (MRI), nerve conduction studies (NCS), and auditory test were normal. The physiotherapy and baclofen treatment was started for spasticity. Case 2: A 7-year-old girl, the sister of the case 1 was brought gait disturbance and cognitive impairment. She started walking at 2 years old and was clumsy. At 5 years old, her gait further deteriorated. Her delivery was full-term and neonatal period was uneventful. Physical examination revealed predominantly distal, spastic paraparesis, global hyperreflexia, bilateral Babinski sign and foot drop, with spastic and steppage gait. The Stanford-Binet test was applied and the score was 55. Laboratory investigations, NCS, brain MRI, and auditory test were normal. The physiotherapy and baclofen treatment was started for spasticity. Clinical exome sequencing analysis were performed on the patients using Trusight One kits (Illumina Inc. San Diego, California). As a result of the clinical exome analysis, we identified a novel homozygous mutation at the B4GALNT1gene (c.120G>A p.W40*) which is classified as pathogenic according to ACMG criteria and has not been reported previously. The mutation found was considered to be highly probable cause of disease according to in silico analysis (Sorting Tolerant From Intolerant [SIFT], http://sift.jcvi.org and Mutation Taster; http://www.mutationtaster.org). Additional family screening revealed that both parent had heterozygous mutation. We confirmed that the patients were SPG26 due to clinical and genetically evaluation.
Figure 1: Pedigree of the patient

Click here to view

SPG26 is childhood/adolescence onset of progressive spastic paraplegia, mild/moderate cognitive impairment, developmental delay, dysarthria, cerebellar ataxia and polyneuropathy. Less commonly reported manifestations include skeletal abnormalities (i.e. pes cavus, scoliosis), dyskinesia, dystonia, cataracts, cerebellar signs (i.e. saccadic dysfunction, nystagmus, dysmetria), bladder disturbances, and behavioral problems.[3],[4],[5],[7]

B4GALNT1 encodes b-1,4 N-acetyl-galactosaminyl transferase 1, which catalyzes the transfer of N-acetyl-galactosamine into GM3, GD3, and globotriaosylceramide by a b-1,4 linkage.[8] GM3 synthase, encoded by ST3GAL5, mediates the sialylation of lactosylceramide to form GM3, the root structure for all downstream a-and b-series gangliosides.[9] Mutations in the gene B4GALNT1 cause SPG26. In recent years, cases of SPG26 due to mutation in the B4GALNT1gene have been reported.[3],[4],[5],[7] In 2005, Wilkinson et al.[4] mapped the SPG26 locus on chromosome 12p11.1-12q14 in a Kuwaiti family with autosomal recessive complicated HSP. In another study, Boukhris et al.[8] reported six homozygous B4GALNT1 mutations (five truncating and one missense) in several families originating from the Mediterranean basin, Brazil, and Germany as a likely cause of complex HSP. Wakil et al.[7] described two families with a complicated form of autosomal recessive HSP and report two novel B4GALNT1 mutations. Their present findings along with previous studies suggest similar phenotypic features of SPG26; early disease onset, mental retardation, slow progression with additional variability such as ataxia, peripheral neuropathy, and extrapyramidal features. Also, in addition to these findings, one patient also had an autism-like behavioral disorder. Recently, Lopes et al.[3] reported that four patients, from three Portuguese families, of complicated HSP revealing B4GALNT1 pathogenic variants. They described hearing dysfunction as a feature of SPG26, not previously described in this condition. We detected novel homozygous mutation c.120G>A (p.W40) in the B4GALNT1gene. Also, our patient had not polyneuropathy and hearing loss.

HSP is a clinically and genetically heterogeneous group of diseases. Our current findings Similar phenotypic features of SPG26 in previous studies (early disease onset, mental retardation, slow progression with additional variability such as ataxia, peripheral neuropathy, and extrapyramidal findings). Although clinically suspected, HSPs have similar features, so the diagnosis should be confirmed by genetic testing.

In conclusion, HSPs are clinically and genetically heterogeneous disorders characterized by lower limb spasticity and weakness. SPG26 should be included in the differential diagnosis of lower limb spasticity and weakness when additional ataxia, cognitive deficits, polyneuropathy, and extrapyramidal involvement.

   Declaration of patient consent Top

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

   Financial support and sponsorship Top


   Conflicts of interest Top

There are no conflicts of interest.

   References Top

McMonagle P, Webb S, Hutchinson M. The prevalence of “pure” autosomal dominant hereditary spastic paraparesis in the island of Ireland. J Neurol Neurosurg Psychiatry 2002;72:43-6.  Back to cited text no. 1
Finsterer J, Löscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci 2012;318:1-18.  Back to cited text no. 2
Lopes C, Silveira F, Nadais G, Leão. Expanding the phenotype of spastic paraplegia 26: report of 4 cases with hearing dysfunction. Ann Musculoskelet Med 2019;3:014-7.  Back to cited text no. 3
Wilkinson PA, Simpson MA, Bastaki L, Patel H, Reed JA, Kalidas K, et al. A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet 2005;42:80-2.  Back to cited text no. 4
Dad R, Walker S, Scherer SW, Hassan MJ, Alghamdi MD, Minassian BA, et al. Febrile ataxia and myokymia broaden the SPG26 hereditary spastic paraplegia phenotype. Neurol Genet 2017;3:e156.  Back to cited text no. 5
Xu YH, Barnes S, Sun Y, Grabowski GA. Multi-system disorders of glycosphingolipid and ganglioside metabolism. J Lipid Res 2010;51:1643-75.  Back to cited text no. 6
Wakil SM, Monies DM, Ramzan K, Hagos S, Bastaki L, Meyer BF, et al. Novel B4GALNT1 mutations in a complicated form of hereditary spastic paraplegia. Clin Genet 2014;86:500-1.  Back to cited text no. 7
Boukhris A, Schule R, Loureiro JL, Lourenço CM, Mundwiller E, Gonzalez MA, et al. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 2013;93:118-23.  Back to cited text no. 8
Inokuchi JI, Go S, Yoshikawa M, Strauss K. Gangliosides and hearing. Biochim Biophys Acta Gen Subj 2017;1861:2485-93.  Back to cited text no. 9


  [Figure 1]


Previous Article   Next Article


   Ahead of print
     Search Pubmed for
    -  Incecık F
    -  Herguner OM
    -  Bozdogan ST

    Declaration of p...
    Financial suppor...
    Conflicts of int...
    Article Figures

 Article Access Statistics
    PDF Downloaded4    

Recommend this journal