|Year : 2022 | Volume
| Issue : 3 | Page : 73-75
Twisting tale of neuropathy in a toddler
Aarthi Balaji1, Smilu Mohanlal1, Ashraf V Valappil2, Divya Pachat3, VP Tushar2
1 Department of Pediatric Neurology, Aster Malabar Institute of Medical Sciences, Kozhikode, Kerala, India
2 Department of Neurology, Aster Malabar Institute of Medical Sciences, Kozhikode, Kerala, India
3 Department of Medical Genetics, Aster Malabar Institute of Medical Sciences, Kozhikode, Kerala, India
|Date of Submission||11-May-2023|
|Date of Decision||16-Jul-2023|
|Date of Acceptance||17-Jul-2023|
|Date of Web Publication||29-Aug-2023|
Dr. Smilu Mohanlal
Department of Pediatric Neurology, Aster Malabar Institute of Medical Sciences, Kozhikode, Kerala
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Balaji A, Mohanlal S, Valappil AV, Pachat D, Tushar V P. Twisting tale of neuropathy in a toddler. Pediatr Companion 2022;1:73-5
| Introduction|| |
Subacute onset ataxia and recurrent falls can be the initial symptom of chronic inflammatory demyelinating polyneuropathy (CIDP). When CIDP-like presentation is seen in a child, an underlying genetic etiology must be considered. We hereby present a toddler who presented with peripheral neuropathy with partial response to immunotherapy which later turned out to be metachromatic leukodystrophy (MLD).
| Case report|| |
A 2-year-old boy, born of nonconsanguineous marriage, presented with paralytic squint, lower limb weakness, recurrent falls, and irritability of 6 months duration. Antenatal and postnatal periods were unremarkable. Premorbid, he was a cognitively normal child who was able to speak around 5–8 words and was able to walk. No family history of neurological illnesses. The child had undergone surgical correction for the squint 4 months ago but within 2 months postsurgery, squint recurred. Neuroimaging before the surgery was normal. Child presented to our center when he had a recurrence of squint postsurgery. On examination, the child was alert but irritable with bilateral paralytic esotropic squint (left > right). Power in the upper and lower limbs was 4/5, and the child could stand when made to with support. Deep tendon reflexes were absent. There were no other systemic abnormalities on examination.
In the setting of motor regression, squint, irritability with areflexia, and clinical possibilities considered were demyelinating polyneuropathy (hereditary like Charcot Marie tooth variants (CMT) or acquired like post coronavirus disease [COVID] phenomenon) versus remote possibility of leukodystrophies with peripheral neuropathy. Nerve conduction study showed prolonged distal motor latency and decreased conduction velocity with normal amplitude in the right median nerve. F waves were absent in the right peroneal and right tibial nerve—amounting to definite CIDP as per European Federation of Neurological Societies/Peripheral Nerve Society diagnostic criteria for CIDP electrodiagnostic criteria.
Magnetic resonance imaging (MRI) brain with contrast was normal. MRI spine showed distal cord thickening, with significant T2 hyperintensities in the distal nerve roots of the cauda equina [Figure 1]. Initial laboratory investigations such as complete blood count, liver and renal functions, blood lactate, and ammonia were within normal limits. MRI brain was unremarkable. Cerebrospinal fluid analysis revealed normal cell count with normal glucose levels. CSF protein levels were elevated to 107 mg/dL. CSF antiganglioside panel was negative. Clinical diagnosis of CIPD was made. COVID IgG antibody levels were elevated to 26.83 AU/mL.
|Figure 1: Axial T1 with contrast showing diffuse thickening and marked enhancement of cauda equina nerve roots bilaterally|
Click here to view
The child was pulsed with methylprednisolone for 5 days and intravenous immunoglobulin of 2 g/kg was given and discharged on oral steroids at 1 mg/kg/day. The child initially improved over 3 weeks wherein he started walking with support; however, after 6 weeks, the child had recurrence of squint and inability to walk. In view of inadequate therapeutic response ,genetic study was done using whole exome sequencing that revealed homozygous class I pathogenic variant in the arylsulfatase A (ARSA) gene, autosomal recessive—MLD. The child is now aged 3 years and has seizures, pseudobulbar dysfunction, and regression in both motor and cognitive domains.
Infantile MLD is an autosomal recessive disorder with motor and cognitive regression caused by a deficiency in the enzyme activity of ARSA due to a mutation in ARSA gene. Peripheral neuropathy may often be the initial presenting symptom, along with uniform slowing of both motor and sensory nerve conduction velocities and risk of developing unsteady gait and ataxia.
Strabismus is rarely reported and is considered to occur as a precursor to motor weakness and emergence of white matter abnormalities on imaging but our patient had presented with strabismus. Acute onset paralytic esotropia has been reported in less than 10 cases worldwide as an early presenting symptom. Imaging may still be normal without contrast enhancement of cranial nerves similar to our case. Peripheral nervous system involvement in MLD is reported as the initial presenting symptom that is detected with clumsiness of gait, weakness, and areflexia. A total of 80% of cases are known to have peripheral neuropathy in late infantile MLD. Spasticity and hyperreflexia are often present initially followed by areflexia. In a study by Bindu et al., electrophysiological evidence of demyelinating and length-dependent sensory-motor neuropathy was observed in all cases even in the presence of hyperreflexia.
A total of 25% of cases with late infantile MLD are reported to have normal neuroimaging at initial presentation. Nevertheless, the white matter abnormalities ensue very soon, and children are often bedridden by a mean age of 2 years and 8 months. Severity of peripheral neuropathy does not predict central nervous system (CNS) disease manifestations in untreated patients. But invariably all children with pyramidal signs and bulbar palsy develop peripheral neuropathy.
There are various treatment options other than transplant, which are in clinical trials: (1) Enzyme replacement therapy and (2) CNS-administered adenovirus-associated gene therapy. Hematopoietic stem cell transplant. All of these modalities have variable results in the course of late infantile MLD.
Though allogeneic hematopoietic stem cell transplant (HSCT) is offered to patients in the phase when neuroimaging is normal, 59% of cases are reported to decline posttransplant, thus making the decision of transplant difficult to accept for caregivers. HSCT is a relatively more promising option in patients with CNS signs rather than isolated peripheral neuropathy. Peripheral demyelination can remain static or worsen after HSCT.
Intrathecal enzyme replacement therapy and Anti Adenovirus 9 antibody vector-mediated gene replacement therapy are under phase I/II clinical trials and are yet to be explored in the human population.
In our case, the initial presentation of squint, areflexia, hypotonia, and NCS fitting into CIDP criteria with cauda equina enhancement with normal MRI brain made us believe that we are dealing with a peripheral neuropathy that could be secondary to post-COVID phenomenon/CMT; however, the genetic confirmation of MLD came as a twist in our tale.
| Conclusion|| |
When a toddler presents with polyneuropathy and is unresponsive/partially responsive to immunotherapy, the possibility of hereditary neuropathy must be strongly considered and a genetic testing is recommended.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Liaw HR, Lee HF, Chi CS, Tsai CR Late infantile metachromatic leukodystrophy: Clinical manifestations of five Taiwanese patients and genetic features in Asia. Orphanet J Rare Dis 2015;10:144.
Beerepoot S, Wolf NI, Wehner K, Bender B, van der Knaap MS, Krägeloh-Mann I, et al
. Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile metachromatic leukodystrophy. Eur J Paediatr Neurol 2022;37:87-93.
Beerepoot S, Nierkens S, Boelens JJ, Lindemans C, Bugiani M, Wolf NI Peripheral neuropathy in metachromatic leukodystrophy: Current status and future perspective. Orphanet J Rare Dis 2019;14:240.
Bindu PS, Mahadevan A, Taly AB, Christopher R, Gayathri N, Shankar SK Peripheral neuropathy in metachromatic leucodystrophy. A study of 40 cases from south India. J Neurol Neurosurg Psychiatry 2005;76:1698-701.
Eichler F, Grodd W, Grant E, Sessa M, Biffi A, Bley A, et al
. Metachromatic leukodystrophy: A scoring system for brain MR imaging observations. AJNR Am J Neuroradiol 2009;30: 1893-7.
Jabbehdari S, Rahimian E, Jafari N, Sanii S, Khayatzadehkakhki S, Nejad Biglari H The clinical features and diagnosis of metachromatic leukodystrophy: A case series of Iranian pediatric patients. Iran J Child Neurol 2015;9:57-61.
Fumagalli F, Calbi V, Sora MGN, Sessa M, Baldoli C, Rancoita PM, et al
. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: Long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet 2022;399:372-83.
Lamichhane A, Rocha Cabrero F Metachromatic leukodystrophy. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2022
Hironaka K, Yamazaki Y, Hirai Y, Yamamoto M, Miyake N, Miyake K, et al
. Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector. Sci Rep 2015;5:13104.