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. 2020 May 1;15(1):109.
doi: 10.1186/s13023-020-01355-2.

The natural history of infantile neuroaxonal dystrophy

Fadie D Altuame  1 , Gretchen Foskett  2 , Paldeep S Atwal  3 , Sarah Endemann  2 , Mark Midei  2 , Peter Milner  2 , Mustafa A Salih  4 , Muddathir Hamad  4 , Mohammad Al-Muhaizea  5 , Mais Hashem  6 , Fowzan S Alkuraya  7
Affiliations

The natural history of infantile neuroaxonal dystrophy

Fadie D Altuame et al. Orphanet J Rare Dis. .

Abstract

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.

Keywords: INAD; Infantile neuroaxonal dystrophy; Molecular genetics; Natural history.

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Conflict of interest statement

Peter Milner, Sarah Endemann, Mark Midei, Paldeep Atwal, are employed by, and hold stock in Retrotope, Inc. All other authors have no potential conflicts of interest. All authors confirm that the content of the article has not been influenced by the sponsor.

Figures

Fig. 1
Fig. 1
Timeline of the Natural History of INAD. Timeline graph representing the mean age (yellow box) at which each milestone (blue box) was lost
Fig. 2
Fig. 2
Radiographic Imaging Data for the Study Cohort. a-d: Representative MRI images for the affected individuals P14 (at age 3 years 2 months), P15 (at age 3 years 2 months), P19 (at age 4 years 3 months), and P20 (at age 4 years 7 months) showing cerebellar atrophy. e: MRI at 3 years and 2 months showing altered signal intensity in the globus pallidus of P15. f: MRI at 4 years and 3 months showing bilateral symmetrical subtle low T2 signals noted in the globus pallidus, substantia nigra, and dentate nuclei of P19. g: MRI at 6 years and 9 months showing bilateral globus pallidus low signal intensity likely representing iron deposition in P18. h: MRI at 6 years and 9 months showing brain, cerebellar and brainstem atrophic changes in P18. i: CT at 6 years showing global brain atrophy in P26
Fig. 3
Fig. 3
Age at Initial Loss of Milestones By Variant Type With Standard Errors (*p value <0.05)
See this image and copyright information in PMC

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