Infantile onset ascending hereditary spastic paralysis

Abstract

A 3½-year-old girl, presented with delayed motor development and increased tone in lower limbs along with tight tendoachilles, toe walking and bilateral clonus. There were normal antenatal and perinatal period, however, after birth there was twitching of her lower limbs. Examination showed lower limb spasticity.

Brain and spinal MRI along with EEG were normal. Serum amino acids revealed hyperprolinemia type 1. Hereditary spastic paraplegia gene panel confirmed a homozygous pathogenic variant in ALS2 gene, confirming a diagnosis of infantile onset ascending hereditary spastic paraparesis. She was fitted with ankle-foot orthotics, uses a Kaye walker and is on baclofen and diazepam as she can experience spasticity and painful muscle cramps. She is being managed by a multidisciplinary team involving paediatrician, paediatric neurologist, physiotherapist, occupational therapist, speech and language therapist, dietitian and social worker. Infantile onset ascending hereditary spastic paraplegia represents a rare cause of early onset spasticity with a progressive prognosis.

Background

This report describes the diagnosis and management of a rare genetic disorder, with only 30 cases reported in the scientific literature. Infantile onset ascending hereditary spastic paralysis is one of a group of genetic disorders known as hereditary spastic paraplegia. This report highlights that infantile onset ascending hereditary spastic paraplegia represents a rare cause of early onset spasticity with a progressive prognosis.

Case presentation

A 3½-year-old girl was born by spontaneous vaginal delivery weighing 7 lb 8 oz, the first child to non-consanguineous parents without a known family history of neurological disease or disorder. Pregnancy was uneventful, the mother did not take any medications other than pregnacare. Delivery was uncomplicated and she was discharged home with her mother. Mother noticed lower extremities tremors in the early postnatal period with twitching in both lower limbs, often one leg at a time, during daytime and sometimes while asleep. She developed delayed motor milestones, that is, delayed sitting without support (10 months), W sitting position, difficulty pulling to stand, toe walking and cruising at 16 months of age. Her development otherwise was on track and there was no upper limb involvement.

In view of toe walking and inability to pull to stand she was linked up initially with physiotherapy. However, there was no evidence of improvement even with physiotherapy input. Her examination at 19 months of age revealed a non-dysmorphic child who was alert, socially interactive and with a normal cognitive ability. Neurologically, lower limbs were hypertonic, deep tendon reflexes were brisk at ankles and knees along with bilateral clonus. Cranial nerves were intact, and no tremor or ataxia was noted. The rest of the systemic examination was normal.

Brain and spinal MRI were normal. Serum amino acids showed hyperprolinemia type 1. Based on these she was referred to a paediatric neurologist and metabolic services.

Investigations

Initial investigation revealed hyperprolinemia type 1, subsequently confirmed as a result of a missense pathogenic variant (c.1322T>C). Cranial ultrasound was done, and results were limited due to small anterior fontanelle. MRI of brain and spine and electroencephalograph were normal. Hereditary spastic paraplegia next generation sequencing (NGS) gene panel revealed a novel homozygous pathogenic variant (c.2527C>T) in exon 13 of the ALS2 gene. Both parents are heterozygous for the same pathogenic mutation. The variant is predicted to result in targeting of the mRNA for nonsense-mediated decay or the production of truncated protein. Segregation studies confirmed that the variant was in trans.

Array comparative genomic hybridization analysis was performed using an oligonucleotide array with ~60 000 probes across the genome. It revealed a loss of approximately 148 kb in the short arm of chromosome 10 at band 10p 13 between base pair coordinates 16 446 128 and 16 594 014. This gene contains 2 OMIM genes, PTER (OMIM 604446) and C1QL3 (OMIM 615227). Follow-up CGH array from the mother demonstrated that she carries the same loss in 10p 13 confirming the imbalance is maternally derived. The contribution of this event in relation to the clinical phenotype is currently uncertain.

Differential diagnosis

The top differential diagnoses are juvenile primary lateral sclerosis and juvenile amyotrophic lateral sclerosis which have the same genetic cause as infantile onset ascending hereditary spastic paraplegia and similar presentation. Acquired antenatal insult resulting in periventricular leukomalacia can result in non-progressive diplegic cerebral palsy. Spinal cord lesions were an alternative differential diagnoses but having had a normal brain and spinal MRI made this unlikely. Other neurological disorders such as Pelizaeus-Merzbacher disease, Canavan disease and purine nucleoside phosphorylase deficiency can present with early onset spasticity, but specific clues can be found on neuroimaging and/or metabolic markers.

Treatment

Symptomatic management given the poor prognosis involved a multidisciplinary team including paediatrician, paediatric neurologist, physiotherapist, occupational therapist, speech and language therapist and social worker with subsequent involvement of palliative care consultant. She was commenced on anti-spasticity medications like baclofen and diazepam as she suffered painful muscle spasms, moreover, she has had hypersalivation for which anticholinergics were used.

Outcome and follow-up

She is under the care of paediatrician and other members of the multidisciplinary team, she used a Kaye walker and fitted with ankle-foot orthotics, however, she is clinically deteriorating with progressive loss of developmental skills.

Discussion

Infantile onset ascending hereditary spastic paralysis (IAHSP) is one of a spectrum of three neurological disorders that happen as a result of ALS2 gene-related genetic disorder which entails degeneration of the pyramidal tracts upper motor neurons. Clinical findings and the molecular genetic testing are the cornerstone in reaching the diagnosis.¹

Infantile onset ascending hereditary spastic paralysis (IAHSP) is one of a collection of genetic diseases called hereditary spastic paraplegias, it is featured by ascending spastic paralysis that usually begins in the lower limbs (pure type) within the first 2 years of life and progressively affects the upper limbs and head and neck (complicated type). Children have a normal examination at birth. Early manifestations of the disease include hyperreflexia and muscle twitching in lower limbs followed by tightness and weakness. Although patients who have the complicated type develop anarthria along with upper and lower limbs paralysis, their cognition remains preserved. It is a rare disease with at least 30 cases reported in the literature. IAHSP is inherited as an autosomal recessive pathogenic variant that affects the ALS2 gene which encodes ALSIN protein the vast majority of which is produced in the brain. ALSIN protein activates multiple proteins in the body called GTPases which in turn plays a vital role in the formation of fundamental neuronal structures like a cell membrane, neuronal axons and dendrites, moreover, it helps in the process of transferring molecules from the cell membrane to the interior of the cell body, all these aid in delivering the neuronal impulse effectively. Thus, pathogenic variants in ALS2 gene affect the neuronal structure and function resulting in atrophied neurons which is a characteristic feature of this condition.²

Infantile onset ascending hereditary spastic paraparesis syndrome is inherited as a heterogeneous condition, and there is no single phenotypic feature that predicts whether an index case carries the ALS2 pathogenic variant. The aforementioned conclusion is based on studying 16 patients from 11 unrelated families from north Africa and Europe who presented with typical characteristics of IAHSP, where affected children developed paraplegia within 2 years of birth and upper limb involvement towards the end of the first decade. By the second decade, the children were tetraplegic, anarthria, dysphagic with abnormal eye movements. Corticospinal and corticobulbar tracts are selectively affected without lower motor neuron involvement. MRI showed normal findings in young children but revealed atrophy of the cerebral cortex in the oldest along with hyperintense signals affecting the caudal part of the internal capsule.³

Learning points.

• Infantile onset ascending hereditary spastic paralysis (IAHSP) should be considered in cases of early onset spasticity when neuroimaging is normal or does not suggest an acquired cause

• IAHSP can be included in the differential diagnosis of cerebral palsy but is progressive

• Multidisciplinary team input is invaluable in the management of life-limiting conditions with poor prognoses.

Ethics statements

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