EDITORIAL

Defects of RNA metabolism in the pathogenesis of spinal muscular atrophy

Enrico Bertini, MD Henry Houlden, MD, PhD

Correspondence to Dr. Bertini: [email protected] Neurology® 2014;82:1–2

Childhood spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous group of inherited neuromuscular disorders characterized by degeneration of motor neurons of the spinal cord leading to progressive atrophy of skeletal muscles and paralysis. The most frequent form is inherited as an autosomal recessive trait and is due to mutations of the survival motor neuron 1, telomeric (SMN1)1 gene manifesting with a proximal distribution of weakness of legs and arms. The other forms of SMAs are rare disorders differing by their mode of inheritance, the topography of the muscle deficit, or the association with other neurologic abnormalities. The SMA with respiratory distress (SMARD) phenotype was first noticed approximately 40 years ago,2 and 15 years later it was defined as a variant of infantile SMA by the early distal and diaphragmatic involvement.3 It became a genetically defined autosomal recessive condition 10 years ahead of positional cloning strategy4 and is currently defined as SMARD type 1 (SMARD1). SMARD is a well-known distal variant of SMA but genetic heterogeneity is well recognized,5 and although it shares a similar distribution of distal weakness with the LAS1L-related SMA, IGHMBP2-related SMARD1 does not seem to have a congenital onset.5,6 Furthermore, another group of treatable autosomal recessive motor neuron disorders defined as BrownVialetto-Van Laere syndrome, related to mutations in SLC52A2 and SLC52A3 encoding riboflavin transporter RFT3 and RFT2, should be considered in the differential diagnosis with SMARD1 because they have postnatal onset and frequently involve distal limbs and typically the diaphragmatic function.7 In this issue of Neurology®, Butterfield et al.8 describe a novel severe and early fatal congenital form of motor neuron disease in a boy who had diaphragmatic involvement and respiratory insufficiency, thus clinically overlapping with SMARD1, but lacking a mutation in the IGHMBP2 gene. By exome sequencing, these authors detected a novel de novo missense mutation, c.1430G.A, p.Ser477Asn, in LAS1L, a

gene located in Xq12 with a role in ribosomal biogenesis.9 This is the second X-linked gene related to a severe, very rare motor neuron disease with congenital onset after the detection of defects in the ubiquitinactivating enzyme UBE110 that maps to Xp11.23. UBE1 is able to transfer ubiquitin to a wide range of E2 substrates and thereby affects the ubiquitinproteasome machinery. E2 proteins have various roles within the cell and have important roles in target degradation (proteasomal pathways) and target modification for regulatory purposes (nonproteasomal pathways). The biochemical process of Ub/UBL conjugation is initiated by the adenosine triphosphate– dependent E1 enzyme, followed by transfer to the active site cysteine of E2 enzymes.11 This condition is clinically distinguishable by congenital fractures and contractures that usually remain throughout the child’s life. Other rare autosomal recessive SMA disorders with congenital onset, besides the SMN-related SMA type 0,12 are the lethal congenital contracture syndrome 1 (LCCS1) and the lethal arthrogryposis with anterior horn cell disease (LAAHD) phenotypes, both related to mutations in nucleoporin GLE1GLE1,7 a nuclear protein with a leucine-rich nuclear export sequence essential for poly(A)1 RNA export. LCCS1 is characterized by fetal akinesia leading to multiple joint contractures and death in utero before 32 weeks’ gestation.13 Two additional genes are responsible for LCCS, defined as LCCS2 (receptor tyrosine-protein kinase erbB-3; ERBB3)14 and LCCS3 (type I phosphatidylinositol-4-phosphate 5-kinase; PIP5K1C)15 phenotypes. While GLE1 functions in the terminal export process of poly (A)1 RNA from the nucleus to the cytoplasm via inositol hexakisphosphate (IP6)-dependent activation, both ERBB3 and PIP5K1C are involved in the synthesis of inositol hexakisphosphate (InsP6)16 linking the phosphatidylinositol pathway to the termination of translation interplay of messenger RNA and ribosomal RNAs.

See page XXX From the Unit of Neuromuscular and Neurodegenerative Disorders (E.B.), Laboratory of Molecular Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy; and Molecular Neuroscience Department (H.H.), UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, University College London, UK. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2014 American Academy of Neurology

ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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Finally, another recently defined congenital autosomal recessive SMA, pontocerebellar hypoplasia type 1 (PCH1), is characterized by hypoplasia of the olivary nuclei, pons, and cerebellum and progressive anterior horn cell loss. Hypotonia and weakness are usually noted in the newborn period and can be associated with congenital joint contractures. Early tongue fasciculations occur in other SMA conditions; however, ocular, bulbar, and facial abnormalities are distinctive key features. Homozygous or compound heterozygous mutations in human exosome component 3 (EXOSC3), also known as the ribosomal RNA–processing protein 40 (RRP40), a noncatalytic subunit of the exosome complex involved in the processing and turnover of several RNA species, have recently been related to PCH1.17 This report on a mutation in LAS1L thus confirms an emerging concept that abnormalities of RNA metabolism have a major role in the pathogenetic mechanisms of several motor neuron disorders.18 As a final consideration, the phenotypic spectrum of the LAS1L-related SMA is lacking in this report because it describes a single patient, and screening for additional suggestive patients was limited to exon 11. Although the impression from this report is that the LAS1L-related SMA seems to be a very rare condition, we cannot exclude that extensive screening of a large cohort of patients with a suggestive undefined motor neuron disease will amplify the number and increase the phenotypic spectrum of LAS1L-related SMA. AUTHOR CONTRIBUTIONS

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Enrico Bertini: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Henry Houlden: drafting/revising the manuscript, acquisition of data.

STUDY FUNDING

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No targeted funding reported.

DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

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April 15, 2014

ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Defects of RNA metabolism in the pathogenesis of spinal muscular atrophy.

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