Elevated aspartate aminotransferase and lactate dehydrogenase levels are a constant finding in <i><scp>PLA</scp>2G6</i>‐associated neurodegeneration

Kraoua, Ichraf; Romani, Marta; Tonduti, Davide; Benrhouma, H.; Zorzi, Giovanna; Zibordi, Federica; Ardissone, Anna; Gouider-Khouja, N.; Youssef–Turki, Ilhem Ben; Nardocci, Nardo; Valente, Enza Maria

doi:10.1111/ene.12927

Cited by 4 publications

(3 citation statements)

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“…Thus, MRI provides limited benefit for early INAD diagnosis. Notably, in PLA2G6 -mutant patients, the observation of elevated AST and LDH levels ( 22 , 23 ), which were confirmed in our proband, raises the possibility that these two enzymes represent potential biomarkers of INAD. Our findings also indicated reduced creatinine levels and elevated ALP/CK-MB levels in the proband, indicating a widespread enzyme metabolism disorder and, possibly, kidney, heart, and multiple tissue damage.…”

Section: Discussionsupporting

confidence: 74%

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

Lyu,

Wang,

Lin

et al. 2024

Transl Pediatr

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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.

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Section: Discussionsupporting

confidence: 74%

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

Lyu,

Wang,

Lin

et al. 2024

Transl Pediatr

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“…Screening bloodwork can also be a powerful tool, providing clues about the potential diagnosis of INAD. It has been previously reported in the literature that AST and LDH elevations are consistent in patients with INAD [25]. A similar pattern is not reliably reproduced among patients with other conditions in the PLA2G6disease spectrum and thus it has been proposed that AST and LDH elevations are relatively specific for PLA2G6-related INAD.…”

Section: Discussionmentioning

confidence: 85%

The natural history of infantile neuroaxonal dystrophy

Altuame

Foskett

Atwal

et al. 2020

Orphanet J Rare Dis

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Background: Infantile 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 calciumindependent phospholipase A2. Objective: We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. Materials and methods: We 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. Results: In 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. Temporofrontal 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/inframe 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). Conclusion: INAD 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.

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“…Screening bloodwork can also be a powerful tool, providing clues about the potential diagnosis of INAD. It has been previously reported in the literature that AST and LDH elevations are consistent in patients with INAD (25). A similar pattern is not reliably reproduced among patients with other conditions in the PLA2G6-disease spectrum and thus it has been proposed that AST and LDH elevations are relatively specific for PLA2G6-related INAD.…”

Section: Discussionmentioning

confidence: 84%

The Natural History of Infantile Neuroaxonal Dystrophy

Altuame

Foskett

Atwal

et al. 2020

Preprint

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Background Infantile 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. Objective We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. Materials and Methods We 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. Results In 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). Conclusion INAD 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.

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Elevated aspartate aminotransferase and lactate dehydrogenase levels are a constant finding in PLA2G6‐associated neurodegeneration

Cited by 4 publications

References 4 publications

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

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

The natural history of infantile neuroaxonal dystrophy

The Natural History of Infantile Neuroaxonal Dystrophy

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