Year : 2022 | Volume
: 8 | Issue : 2 | Page : 206--208
A rare case of the complex phenotype of hereditary spastic paraparesis due to a mutation in a novel gene variant
B Jude Antonieo Raja, Sakthi Abirami, Priya Jose, Peter Prasanth Kumar Kommu
Department of Paediatrics, Pondicherry Institute of Medical Sciences, Puducherry, India
Department of Paediatrics, Pondicherry Institute of Medical Sciences, Kalapet, Puducherry - 605 014
Hereditary spastic paraplegia (HSP), is a heterogeneous group of corticospinal tract disorders leading to progressive lower limb weakness and spasticity. Recessive mutations in DDHD2 characteristically involve early onset delay in motor and cognitive milestones coupled with spasticity. The complex nature of HSP is always confounding for appropriate management. An 11-year-old boy was brought by his parents for developmental delay noticed from 7 months of age and was diagnosed to have possible spastic cerebral palsy initially. Due to increasing spasticity, he underwent tendon release surgery for achilles and iliopsoas at 4 years of age. Now, he presented to us with increasing stiffness in his lower limbs even after regular physical therapy and myoclonic jerks. He had severe spasticity in the lower limbs with a power of 4/5. His activities of daily living were restricted due to severe spasticity. The lower limb deep tendon reflexes are exaggerated with positive Babinski sign and Scissoring of gait. He also had a mild intellectual disability. He was started on symptomatic management with muscle relaxants. Clinical exome sequencing showed a novel homozygous nonsense variation in exon 6 of DDHD2 gene. Prenatal genetic counseling was given for the next pregnancy and hence chorionic villus sampling for the variant testing of the developing fetus was done. The reports revealed a heterozygous state and asymptomatic carrier, unlikely to be affected by DDHD2-associated phenotype (spastic paraplegia genes 54). HSP should be considered when there is global developmental delay and increasing spasticity in lower limbs despite rehabilitation therapies.
|How to cite this article:|
Antonieo Raja B J, Abirami S, Jose P, Kumar Kommu PP. A rare case of the complex phenotype of hereditary spastic paraparesis due to a mutation in a novel gene variant.J Curr Res Sci Med 2022;8:206-208
|How to cite this URL:|
Antonieo Raja B J, Abirami S, Jose P, Kumar Kommu PP. A rare case of the complex phenotype of hereditary spastic paraparesis due to a mutation in a novel gene variant. J Curr Res Sci Med [serial online] 2022 [cited 2023 May 28 ];8:206-208
Available from: https://www.jcrsmed.org/text.asp?2022/8/2/206/364502
Hereditary spastic paraplegia (HSP), alternatively referred to as Strümpell–Lorrain syndrome, is a series of inherited neurologic illnesses caused by degeneration of the upper motor neurons. The age of onset has a wide range starting from infancy to the eighth decade. Since the discovery of HSP, more spastic paraplegia genes (SPG) have been identified as being involved in the etiology of this neurological disorder. With an estimated prevalence of 3–10 per 1 lakh, they are among the common causes of motor neuron disease (MND). Clinical features such as global developmental delay and increasing spasticity can occur despite regular intensive physical therapy care. It is a close mimicker of cerebral palsy but HSP will be progressive when observed over the years and a specific cause cannot be identified unless a genetic analysis is done. Hereby, we report a rare case of the complex phenotype of hereditary spastic paraparesis due to a novel mutation in the DDHD2 gene.
An 11-year-old boy, a second-born child to a second-degree consanguineous married couple with uneventful antenatal history and delivered vaginally at term, weighing 2700 gm with a smooth perinatal transition. The parents noticed developmental delay at 7 months of life and were diagnosed to have possible spastic cerebral palsy of unknown etiology and then he was commenced on physical therapy and occupational therapy. Due to increasing spasticity, he underwent tendon release surgery for achilles and iliopsoas at 4 years of age. Magnetic resonance imaging of the brain demonstrated symmetrical hyperintense signals in the central tegmental tracts with thinned-out corpus callosum (Ear of lynx appearance). At 6 years of age, he had one episode of generalized seizure for which antiseizure medications were taken only for 2 months but no further seizure episodes. At 11 years, he presented to us with increasing stiffness of lower limbs even after regular physical therapy and myoclonic jerks. There were no facial dysmorphism or neurocutaneous markers. He had severe spasticity in the lower limbs with a power of 4/5. His activities of daily living were restricted due to severe spasticity. The lower limb deep tendon reflexes are exaggerated with positive Babinski sign and Scissoring of gait. He also had a mild intellectual disability with a score of 62 when assessed with the Malin's Intelligence Scale for Indian children. He was started on symptomatic management with muscle relaxants. Tandem mass spectrometry and electroencephalogram were within normal limits. His basic blood investigations revealed microcytic hypochromic anemia with mild eosinophilia, normal liver function, renal function tests, and normal urine analysis. Serum homocysteine was 21.85 μmol/L (normal value <10 μmol/L). Arterial lactate was 24 mg/dl (4.5–19.8 mg/dl).
Clinical exome sequencing showed a novel homozygous nonsense variation in exon 6 of the DDHD2 gene (chr8: g. 38240346C > T; Depth: 126x) that results in a stop codon and premature truncation of the protein at codon 232 (p. Arg232Ter; ENST00000397166.7). This variant has been validated in a Sanger sequencing analysis.
Meanwhile, the mother conceived and consulted us when she was at 18 weeks of pregnancy. Considering the parent's wish to have a normal child, prenatal genetic counseling was given explaining the necessity of chorionic villus sampling for the variant testing of the developing fetus. The reports revealed a heterozygous state and asymptomatic carrier, unlikely to be affected by DDHD2-associated phenotype (SPG 54). Hence, the pregnancy was continued. She has delivered a healthy male baby and he is developmentally normal at 3 months of age.
HSP is a set of corticospinal tract-related neurodegenerative illnesses. They present with lower extremity spasticity and weakness. Our child had HSP-like characteristics such as progressive leg stiffness, gait abnormalities, and good muscle power despite an increased tone in the lower limbs. Our child has complicated HSP with infantile-onset.
As he also had an episode of seizure and mild intellectual disability along with other features. SPG21, AMPD2, AP4B1, AP4E1, AP4M1, AP4S1, AP5Z1, CYP2U1, ENTPD1, MARS1, PGAP1, and WDR48 gene can also cause an infantile onset of complicated HSP with recessive inheritance similar to DDHD2 gene. Other conditions such as structural, metabolic, and vascular lesions, myelinating disorders, cerebral palsy-spastic diplegia, MND, and spinocerebellar ataxia. Neoplasms and leukodystrophy had been excluded in this child.
Spastic paraplegia caused by a DDHD2 mutation may result in early-onset stiffness that advances slowly and leads to gross motor delay, leading to a false diagnosis of cerebral palsy. Mutation in genes SPG47, SPG50, SPG51, and SPG52 can cause cerebral palsy-like HSP forms, but our patient with clinical features of cerebral palsy had a mutation resulting in SPG54.
Nicita et al. identified additional novel variants of SPG54, in which epilepsy was not reported, whereas in this novel, a variant of DDHD2 gene recessive mutation, it has been associated with epilepsy. Our patient had only one episode of seizure and was not on regular antiepileptic medications.
Children with HSP due to the DDHD2 gene can have optic atrophy and leukodystrophy which was absent in this child.
Although the frequency of intellectual disability in children with HSP is higher with mutation of the SPG-54 gene according to Erfanian et al., our patient had only mild intellectual disability.
Pascual et al. in a case–control study also demonstrated the “ Ears of the lynx” pattern, which is a pathognomic imaging feature suggesting a pathogenic mutation in HSP patients involving thin corpus callosum which was seen in our patient.
Elsayed et al. observed that almost 80% of genetic forms are clusters of childhood and out of which SPG54 autosomal recessive HSP occurs from infancy. The variant identified in our child is novel and not previously described. Alrayes et al. described one Indian family, with affected offspring bearing a homozygous recessive mutation in the DDHD2 gene (SPG54) similar to our patient. There is no specific treatment for HSP. Daily physical therapy with occupational therapy, drugs to reduce spasticity, and annual assessments by pediatric neurologists remain the mainstay of treatment that this child is already on.
HSP should be considered when there is global developmental delay and increasing spasticity in lower limbs despite rehabilitation therapies. The presence of other complex features such as epilepsy or movement disorders should not be considered a pointer against making a differential diagnosis of HSP. The next-generating sequencing is the investigation of choice in such cases. Hence, genetic confirmation in the proband followed by prenatal counseling comprising a team of the general pediatrician, pediatric neurologist, geneticist, and fetal medicine specialist is rewarding in this scenario.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's mother has given her consent for their son's clinical information to be reported in the journal. The patient's mother understands that their son's name and initials will not be published and due efforts will be made to conceal the patient's identity, but anonymity cannot be guaranteed.
The authors would like to thank Dr. Ranjith Kumar Manoharan, Visiting neurology consultant, PIMS – For his expert opinion on management; Dr. Shanthi Kannan, Clinical Psychologist, Department of Pediatrics, PIMS for her psychological assessment and counseling.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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