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Table of Contents
LETTERS TO THE EDITOR
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1190-1192
 

An Indian child with CONDSIAS due to a novel variant in ADPRHL2 gene


1 The Purple Gene Clinic, Mumbai, Maharashtra, India
2 Dr. Poornima's Neurodiagnosis Clinic, Mumbai, Maharashtra, India
3 Criticare Hospital, Mumbai, Maharashtra, India
4 Division of Molecular Genetics, LifeCell International Pvt Ltd, Chennai, Tamil Nadu, India
5 NM Medical Centre, Mumbai, Maharashtra, India

Date of Submission25-Jun-2022
Date of Decision24-Jul-2022
Date of Acceptance29-Jul-2022
Date of Web Publication20-Oct-2022

Correspondence Address:
Shruti Bajaj
Director and Consultant, The Purple Gene Clinic, 210- Simplex KhushAangan, Vijaykar Wadi, SV Road, Malad West, Mumbai - 400 064, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_558_22

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How to cite this article:
Bajaj S, Shah P, Shah A, Setty PN, Seenappa V, Hingwala D. An Indian child with CONDSIAS due to a novel variant in ADPRHL2 gene. Ann Indian Acad Neurol 2022;25:1190-2

How to cite this URL:
Bajaj S, Shah P, Shah A, Setty PN, Seenappa V, Hingwala D. An Indian child with CONDSIAS due to a novel variant in ADPRHL2 gene. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1190-2. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1190/359346




Dear Editor,

A male child of South-Asian descent, the first issue of a nonconsanguineous union, presented to us at 10.5 years age. The child was born full term, without any significant perinatal red flags. Frequent falls and gait instability were first noted at 2 years of age. The child also had history of poor grip over footwear, bilaterally, suggesting distal symmetrical weakness of the lower limbs. He gained the subsequent motor milestones with delay of 8–10 months. He did not achieve urinary or stool continence. There were no hearing or visual deficits, although he was noted to have convergent squint at 3 years of age. The distal-predominant weakness had a chronic progressive course to gradually involve the hand grip too, over the next 1 year. Further worsening of symptoms was noted at 9 years, following an intercurrent illness, to involve the proximal upper and lower limbs. He was now unable to lift his hand over the shoulders or get up from squatting position. The squint was noted to worsen too. At 10 years, following an episode of acute diarrheal illness, he regressed further. He was subsequently unable to self-feed, climb stairs or walk unassisted. Since the last 2 months, the child reported feeding and swallowing difficulties. Throughout the course, there were no seizures or sensory symptoms.

Examination revealed failure to thrive and short stature with normocephaly. He had bilateral convergent squint and nystagmus. His gait was unstable and ataxic. He had appendicular as well as axial hypotonia. The distal muscles of the hands as well the feet appeared wasted. His hand grip was weak with involvement of the intrinsic muscles of the hands. Bilateral symmetric distal-predominant (2/5) weakness along with proximal weakness (3/5) was appreciated. The deep tendon reflexes were elicitable normally, with the exception of bilateral well-sustained ankle clonus. Plantar response was absent. The joint position sense was impaired at bilateral great toes. Vibration sense was impaired at the medial malleoli. Rest of the sensory examination was normal. He had dysarthria and dysmetria. There was no weakness of the neck or the bulbar muscles. There were no behavioral or extrapyramidal abnormalities. Respiratory efforts were normal. Bilateral testes were undescended.

Review of previous investigations done at 6-years revealed normal blood parameters (viz complete blood count, creatinine-phosphokinase, lactate, liver function test, calcium, serum electrolytes, random blood sugar, thyroid function tests, and serum B12 level) and cerebellar atrophy on MRI brain. Neurophysiology evaluation consisted of electromyography (EMG), nerve conduction studies (NCS), somatosensory evoked potential (SEP), visual evoked potential (VEP), and brainstem electric response audiometry (BERA). All sensory conduction findings were normal. The compound muscle action potential amplitudes (CMAP) were grossly attenuated in the right median and left tibial nerves. Conduction times were mainly normal. Needle EMG revealed neurogenic changes that were mostly distal and symmetrical. The SSEP study showed delayed tibial responses and normal median latencies suggestive of posterior column dysfunction (PCD). The VEP and BERA were normal ruling out optic neuropathy and sensorineural deafness. In summary, neurophysiology evaluation showed evidence of a generalized pure motor, distal symmetrical axonopathy with posterior column involvement at dorsolumbar level.

Repeat MRI brain revealed periventricular and deep white matter abnormalities, superior vermis volume loss and parenchymal abnormalities in the spinal cord at the mid-thoracic level [Figure 1]. The clinico-electrophysiological correlation raised the suspicion of a hereditary motor axonopathy with PCD, likely of a genetic etiology given the early-onset and the chronic progressive course.[1] The variegate, potentially multisystemic spectrum, punctuated by worsening spells following stresses, made us consider mitochondrial disorders as a differential.[2] Juvenile amyotrophic lateral sclerosis was also suspected due to combination of upper motor and lower motor signs, however, the intercurrent worsening of features precipitated by illnesses, was not typical. Distal weakness due to hereditary motor sensory neuropathies or Charcot-Marie-Tooth disease was suspected, but could be differentiated on the basis of normal sensory NCS.
Figure 1: MRI spine and brain reveals diffuse ill-defined T2 hyperintense signal abnormality in the thoracic cord on T2 weighted sagittal (a) and axial (b) images. Diffuse subtle hyperintense signal is seen in the periventricular and deep white matter on T2 weighted axial images of the brain (c). Superior vermian volume loss is seen on mid-sagittal T1 weighted image (d)

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Next-generation sequencing (NGS) based whole-exome sequencing (WES) was ordered. It revealed a novel homozygous loss of function variant in the ADPRHL2 gene [NM_017825.2:c.166C>T; p.(Gln56*)]. This variant is not present in the gnomAD database. It causes a premature stop codon, thus affecting the protein functioning. It was classified as likely pathogenic (class 2) according to the recommendations of the American College of Medical Genetics.[3] The variant was found to be segregating with the parents (both of them being heterozygous carriers for ADPRHL2 gene variant, c.166C>T; p.(Gln56*). This confirmed a rare diagnosis of autosomal recessive childhood-onset neurodegeneration, stress-induced, with variable ataxia and seizures (CONDSIAS) in the child.[4]

CONDSIAS (OMIM #618170) is a rare, cyclically progressive, autosomal recessive neurodegenerative disorder, presenting usually in the first decade of life; the course often exacerbated by febrile illnesses and intercurrent stresses.[4],[5],[6],[7] Literature review reveals our report to be the 33rd case reported globally, only the second one from the Indian Subcontinent.[4],[5],[6],[7]

CONDSIAS, a condition first described as recently as 2018, includes a highly variable spectrum. We should suspect CONDSIAS in the clinical setting of cyclical/episodic worsening of neurodegeneration, ataxia, and seizures. The other clinico-radiological clues of CONDSIAS are summarised in [Table 1]. Evidence of myelopathy, present in our case (revealed by clinical features, SSEP findings, MRI spine findings) was reported only once earlier.[6]
Table 1: Typical features of CONDSIAS and the novel features of CONDSIAS present in our case[3],[4],[5],[6],[7]

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The child was offered physiotherapy and occupational therapy. Role of routine vaccination to minimize intercurrent illnesses was also stressed upon. The parents were explained about the absence of any definitive treatment option for CONDSIAS. A confirmation of CONDSIAS helped the family attain closure to the diagnostic journey spanning over 8 years and understand the associated prognosis.

The child had a chronic gradually regressive course over the next 14-months. He had an acute diarrhoeal illness at 12-years, lasting for 3 days. During this period, he got increasingly incapacitated and nonambulatory; expiring suddenly on the 3rd day of illness.

The mother visited us 4 months later, desiring preconception genetic counseling. She was explained a 25% empiric risk of recurrence at each conception. Having established the causative variant in the proband, we could offer her the following reproductive options[8]:

  1. Natural conception and invasive testing for targeted ADPRHL2-gene by Sanger
  2. In-vitro fertilization (IVF) and preimplantation genetic testing; selective implantation of the “healthy”/unaffected embryos.


The current case of CONDSIAS, the second only from the Indian subcontinent, highlights the strengths of new-age genetic tests in unravelling rare disease (RD) diagnosis and truncating these long diagnostic delays. It underlines the impact of a confirmed diagnosis, even in the absence of definite therapeutic options, in the form of being able to offer prognostication, closure, and reproductive counselling for the future pregnancies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Eggermann K, Gess B, Häusler M, Weis J, Hahn A, Kurth I. Hereditary Neuropathies. Dtsch Arztebl Int 2018;115:91-7.  Back to cited text no. 1
    
2.
Aryan H, Razmara E, Farhud D, Zarif-Yeganeh M, Zokaei S, Hassani SA, et al. Novel imaging and clinical phenotypes of CONDSIAS disorder caused by a homozygous frameshift variant of ADPRHL2: A case report. BMC Neurol 2020;20:291. doi: 10.1186/s12883-020-01873-3.  Back to cited text no. 2
    
3.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.  Back to cited text no. 3
    
4.
Ghosh SG, Becker K, Huang H, Dixon-Salazar T, Chai G, Salpietro V, et al. Biallelic mutations in ADPRHL2, encoding ADP-ribosylhydrolase, lead to a degenerative pediatric stress-induced epileptic ataxia syndrome. Am J Hum Genet 2018;103:431-39.  Back to cited text no. 4
    
5.
Danhauser K, Alhaddad B, Makowski C, Piekutowska-Abramczuk D, Syrbe S, Gomez-Ospina N, et al. Bi-allelic ADPRHL2 mutations cause neurodegeneration with developmental delay, ataxia, and axonal neuropathy. Am J Hum Genet 2018;103:817-25.  Back to cited text no. 5
    
6.
Mishra B, Fatima S, Agarwal A, Radhakrishnan DM, Garg A, Srivastava AK. Dystonia and myelopathy in a case of stress-induced childhood-onset neurodegeneration with ataxia and seizures (CONDSIAS). Mov Disord Clin Pract 2020;8:156-8.  Back to cited text no. 6
    
7.
Ozturk G, Ayaz A, TopcuY, Akyuz G, Unver O, Akbeyaz IH, et al. Stress-induced childhood onset neurodegeneration with ataxia and seizures (CONDSIAS) presenting with torticollis attacks: Phenotypic variability of the same mutation in two Turkish patients. Ann Indian Acad Neurol 2022; doi: 10.4103/aian.aian_314_21.  Back to cited text no. 7
    
8.
Fonda Allen J, Stoll K, Bernhardt BA. Pre- and post-test genetic counseling for chromosomal and Mendelian disorders. Semin Perinatol 2016;40:44-55.  Back to cited text no. 8
    


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