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A rare inherited homozygous missense variant in PLA2G6 influences susceptibility to infantile neuroaxonal dystrophy: a case report.

ABSTRACT:

Background

Infantile neuroaxonal dystrophy (INAD) is an ultra-rare early-onset autosomal recessive neurodegenerative disorder due to PLA2G6 variants. The clinical symptoms of INAD patients display considerable diversity, and many PLA2G6 variants are still not thoroughly investigated in relation to their associated clinical presentations.

Case description

A 16-month-old boy was admitted to our hospital due to regression of acquired motor and speech abilities that had persisted for 4 months. The patient was born to a healthy consanguineous couple after 41 weeks of pregnancy and natural delivery. Before 12 months old, he had normal motor development milestones. On admission, he also showed astasia-abasia, weakness of distal muscles, and diminished patellar tendon reflex. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy. Auditory brainstem response (ABR) indicated moderately severe hearing loss. With chromosome microarray analysis (CMA), we identified several copy number-neutral regions of runs of homozygosity (ROH) in the patient. Whole-exome sequencing (WES) further revealed that the patient harbored a homozygous missense variant NM_003560.2: c.1778C>T, p.Pro593Leu (rs1451486649) in the PLA2G6 gene. In the patient's asymptomatic parents and brother, the PLA2G6 c.1778C>T variant stayed in heterozygous status as confirmed by Sanger sequencing. The patient was finally diagnosed with INAD.

Conclusions

We report an INAD child with a rare PLA2G6 c.1778C>T homozygous missense variant and associated clinical symptoms. The family-based cosegregation analysis reveals that the PLA2G6 c.1778C>T homozygous variant contributes to the pathogenesis of INAD.

SUBMITTER: Lyu Y

PROVIDER: S-EPMC10998992 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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A rare inherited homozygous missense variant in <i>PLA2G6</i> influences susceptibility to infantile neuroaxonal dystrophy: a case report.

Lyu Yongxue Y Wang Tao T Lin Meifang M Qi Fengfeng F

Translational pediatrics 20240320 3

<h4>Background</h4>Infantile neuroaxonal dystrophy (INAD) is an ultra-rare early-onset autosomal recessive neurodegenerative disorder due to <i>PLA2G6</i> variants. The clinical symptoms of INAD patients display considerable diversity, and many <i>PLA2G6</i> variants are still not thoroughly investigated in relation to their associated clinical presentations.<h4>Case description</h4>A 16-month-old boy was admitted to our hospital due to regression of acquired motor and speech abilities that had ...[more]

PMID: 38590380

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Project description:BackgroundMutations in the PLA2G6 gene have been identified in autosomal recessive neurodegenerative diseases classified as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and dystonia-parkinsonism. These clinical syndromes display two significantly different disease phenotypes. NBIA and INAD are very similar, involving widespread neurodegeneration that begins within the first 1-2 years of life. In contrast, patients with dystonia-parkinsonism present with a parkinsonian movement disorder beginning at 15 to 30 years of age. The PLA2G6 gene encodes the PLA2G6 enzyme, also known as group VIA calcium-independent phospholipase A(2), which has previously been shown to hydrolyze the sn-2 acyl chain of phospholipids, generating free fatty acids and lysophospholipids.Methodology/principal findingsWe produced purified recombinant wildtype (WT) and mutant human PLA2G6 proteins and examined their catalytic function using in vitro assays with radiolabeled lipid substrates. We find that human PLA2G6 enzyme hydrolyzes both phospholipids and lysophospholipids, releasing free fatty acids. Mutations associated with different disease phenotypes have different effects on catalytic activity. Mutations associated with INAD/NBIA cause loss of enzyme activity, with mutant proteins exhibiting less than 20% of the specific activity of WT protein in both lysophospholipase and phospholipase assays. In contrast, mutations associated with dystonia-parkinsonism do not impair catalytic activity, and two mutations produce a significant increase in specific activity for phospholipid but not lysophospholipid substrates.Conclusions/significanceThese results indicate that different alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids, which predicts accumulation of PLA2G6 phospholipid substrates and provides a mechanistic explanation for the accumulation of membranes in neuroaxonal spheroids previously observed in histopathological studies of INAD/NBIA. In contrast, dystonia-parkinsonism mutations do not appear to directly impair catalytic function, but may modify substrate preferences or regulatory mechanisms for PLA2G6.

Project description:BackgroundInfantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2.ObjectiveWe aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings.Materials and methodsWe comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD.ResultsIn our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p = 0.04), initial loss of language (p = 0.001), initial loss of fine motor skills (p = 0.009), and initial loss of bulbar skills (p = 0.007).ConclusionINAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.