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Severe Respiratory and Swallowing Disorders in Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic
Edouard Berling1, Philippe Latour1, Klervie Loiselet1
1From the APHP (E.B., C.G.), Service de Neurologie, Hôpital Raymond Poincaré, Garches; APHP (E.B., C.G.), Centre de référence Nord-Est-Ile-de-France, FHU PHENIX; Université de Versailles Saint-Quentin-en-Yvelines (E.B.), U 1179 INSERM, Paris-Saclay; Centre de Biologie Est (P.L., L.V.), Hospices Civils, Lyon; Department of Pediatric Radiology (K.L.), Hôpital Necker-Enfants Malades, Paris; Sorbonne Université (N.B.R., T.E.), UMRS974, - INSERM, Centre de Recherche en Myologie, Institut de Myologie Paris; APHP (N.B.R., E.L., T.E.), Unité de Morphologie neuromusculaire, Centre de référence des maladies neuromusculaires Nord-Est-Ile-de-France; and APHP (T.S.), Sorbonne Université, Service de Neuromyologie, Centre de référence Nord-Est-Ile-de-France, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France.
Insights
This study identifies a novel PTRH2 gene variant in two sisters with infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD1). The findings expand the known phenotype of this rare disorder, emphasizing PTRH2 gene analysis for neuropathy with pancreatic lipomatosis.
Area of Science:
- Genetics
- Neurology
- Endocrinology
Background:
- Infantile-onset multisystem neurologic, endocrine, and pancreatic disease type 1 (IMNEPD1) is a rare autosomal recessive disorder.
- It is characterized by peripheral neuropathy, cerebellar atrophy, intellectual disability, hearing loss, pancreatic insufficiency, hypothyroidism, and dysmorphic features.
- The genetic basis and full phenotypic spectrum of IMNEPD1 are not completely understood.
Purpose of the Study:
- To expand the phenotypic spectrum of IMNEPD1.
- To highlight the importance of analyzing the PTRH2 gene in patients with neuropathy and pancreatic lipomatosis.
Main Methods:
- Clinical evaluation of two elderly sisters with a severe sensorimotor axonal neuropathy.
- Genetic analysis to identify pathogenic variants in the PTRH2 gene.
- Review of classic and potential new manifestations of IMNEPD1.
Main Results:
- Two sisters, aged 73 and 71, presented with severe sensorimotor axonal neuropathy, deafness, and intellectual deficiency.
- Both developed severe respiratory dysfunction and required noninvasive ventilation; one experienced severe dysphagia.
- A novel biallelic PTRH2 variant (c.254A>G, p.Gln85Arg) was identified in both patients, confirming the genetic cause.
Conclusions:
- The PTRH2 gene is implicated in IMNEPD1, with novel variants expanding the known phenotype.
- Severe dysphagia and respiratory insufficiency can be significant complications of IMNEPD1.
- PTRH2 gene analysis is crucial for diagnosing neuropathy associated with pancreatic lipomatosis.
Objectives:
The objective of this study was to expand the phenotypic spectrum of infantile-onset multisystem neurologic, endocrine, and pancreatic disease type 1 (IMNEPD1) and highlight the importance of analyzing the PTRH2 gene in patients with neuropathy presenting with pancreatic lipomatosis.
Methods:
Two sisters, aged 73 and 71 years, respectively, presented a severe, length-dependent sensorimotor axonal neuropathy, associated with deafness and intellectual deficiency.
Results:
They both needed a wheelchair from the fourth decade. They developed a severe respiratory dysfunction, requiring nocturnal noninvasive ventilation from around 50 years of age. The younger sister developed severe dysphagia complicated by aspiration pneumonia. A muscle biopsy of the younger sister was suggestive of mitochondrial myopathy. The youngest presented a complete pancreatic lipomatosis. A biallelic novel likely pathogenic variant within PTRH2, c.254A>G (p.Gln85Arg), was evidenced in both patients.
Discussion:
IMNEPD1 is a rare autosomal recessive disorder caused by sequence variant in the PTRH2 gene and characterized by a peripheral neuropathy, cerebellar atrophy, intellectual disability, hearing loss, pancreatic insufficiency, hypothyroidism, and dysmorphic features. In addition to these classic manifestations of the disorder, severe dysphagia and respiratory insufficiency may develop over the course of the disease and should be systematically screened. PTRH2 gene should be considered in patients with pancreatic lipomatosis and neuropathy.
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