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ARTICLES: M. Sabatelli, F. Madia, A. Conte, M. Luigetti, M. Zollino, I. Mancuso, M. Lo Monaco, G. Lippi, and P. Tonali Natural history of young-adult amyotrophic lateral sclerosis Neurology 2008; 71: 876-881 [Abstract] [Full text] [PDF]

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Natural history of young-adult amyotrophic lateral sclerosis

Yasuhiro Yoshii, Shinji Hadano, Asako Otomo, Kyoko Suzuki, Ken Ikeda, Joh-E Ikeda, Yasuo Iwasaki   (10 February 2009)

Natural history of young-adult amyotrophic lateral sclerosis

Mamede de Carvalho, -   (10 February 2009)

Reply to Yoshii et al. and De Carvalho

Mario Sabatelli, Marco Luigetti, Amelia Conte and Marcella Zollino   (10 February 2009)

Natural history of young-adult amyotrophic lateral sclerosis 10 February 2009
Yasuhiro Yoshii, Toho University Medical Center Omori Hospital 6-11-1 Omori-nishi, Ota-ku, Tokyo #143-8541 JAPAN, Shinji Hadano, Asako Otomo, Kyoko Suzuki, Ken Ikeda, Joh-E Ikeda, Yasuo Iwasaki Send Correspondence to journal: Re: Natural history of young-adult amyotrophic lateral sclerosis yyoshii96097{at}aol.com Yasuhiro Yoshii, et al.	We read with great interest the article by Sabatelli et al. who describe the features of young-adult ALS. [1] There are interesting similarities when comparing the clinical symptoms of sporadic young-onset ALS with the familial form of young-onset ALS. Currently, familial forms of young-onset ALS are known in ALS2 (autosomal recessive, causative gene: ALS2. chromosomal location: 2q33), ALS4 (autosomal dominant, causative gene: SETX, chromosomal location: 9q34), and ALS5 (autosomal recessive, causative gene: unknown, chromosomal location: 15q12-21). Among these three types of ALS, ALS2 is the most frequently investigated. ALS2 is characterized by predominant upper motor neuron phenotype such as spasticity of limbs and facial muscles and caused by ALS2 (initially designed as ALS2CR6) mutations. [2] The ALS2 gene encodes a protein called ALS2/Alsin that plays an important role in membrane/vesicular trafficking and axonal outgrowth in neurons. [3] A neuroprotective role for ALS2 protein against cytotoxicity, oxidative stress, and excitotoxicity has also been documented. [4] The ALS2 mutations are also known to cause other motor neuron diseases including infantile-onset ascending hereditary spastic paraplegia (IAHSP), hereditary spastic paraplegia (HSP), and juvenile recessive form of primary lateral sclerosis (PLS). Hamida et al. reported 12 patients from one family in Tunisia with typical phenotype of ALS2 with males showing the higher prevalence. [5] Symptoms started with pseudobulbar palsy or spastic gait and mean age at onset was 7.2 with a favorable prognosis. Clinical symptoms included apparent spastic pseudobulbar syndrome such as uncontrolled laughter or crying, spastic dysarthria, spastic paraplegia, mild or no muscle atrophy, and no bulbar syndrome. Considering the symptoms of ALS2 and young-onset ALS—especially predominant upper motor neuron phenotype—there are interesting similarities including male dominance, frequent spastic paraparesis, and longer survival. Dr. Sabatelli et al.'s patients demonstrated more arm weakness initially, but interestingly these patients developed pseudobulbar speech in the later stage. Although the ALS2 mutations/variations are not a common cause of sporadic or familial ALS, we believe that exploring the mechanism of ALS2 could be vital in understanding the pathophysiology of young-onset ALS. In addition, dissimilarities of phenotype may suggest entities of other unknown causative mutations among young-adult ALS. References 1. Sabatelli M, Madia F, Conte A, et al. Natural history of young-adult amyotrophic lateral sclerosis. Neurology 2008;71:876-881. 2. Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001;29:166-173. 3. Otomo A, Hadano S, Okada T, et al. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003;12:1671-1687. 4. Hadano S, Kunita R, Otomo A, et al. Molecular and cellular function of ALS2/alsin: implication of membrane dynamics in neuronal development and degeneration. Neurochem Int. 2007;51:74-84. 5. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis): conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain 1990;113:347-363. Disclosure: The authors report no disclosures.
Natural history of young-adult amyotrophic lateral sclerosis 10 February 2009
Mamede de Carvalho, Department of Neurosciences, Hospital de Santa Maria Av Prof Egas Moniz. 1649, Lisbon, Portugal, - Send Correspondence to journal: Re: Natural history of young-adult amyotrophic lateral sclerosis mamedemg{at}mail.telepac.pt Mamede de Carvalho, et al.	We read the article by Sabatelli et al. who concluded that young-adults with ALS survive longer due to the higher prevalence of the spastic phenotype in this population. [1] The table indicates that old-onset cases presenting with the same phenotype had the same survival time compared to young-onset cases. The authors did not mention if this phenotype is an independent prognostic factor in that older-onset group. Thus, it seems that phenotype more than age is the most relevant prognostic factor. The authors cite Ben Hamida et al. [5,6] who studied juvenile familial cases in a particular area of the world. However, the definition of juvenile or young-onset is arbitrary, but the reference to other sporadic cases elsewhere could be more useful. Our review of sporadic ALS cases with onset before 25 years of age [7] was not included in the Sabatelli et al. article. We concluded that young onset patients frequently have a symmetrical presentation and may survive longer. It would be interesting to know if a symmetrical weakness was more frequent in their young-onset group, as ALS is generally asymmetrical. I speculate that many of their spastic patients presented with a relatively symmetric weakness. References 6. Ben Hamida M, Hentati F. Juvenile amyotrophic lateral sclerosis. In: Brown RH, Meininger V, Swash M, eds. Amyotrophic Lateral Sclerosis. London: Martin Dunitz 2000:59-69. 7. Gouveia LO, de Carvalho M. Young onset sporadic amyotrophic lateral sclerosis: a distinct nosologic entity? Amyotr Lat Scler 2007;8:323-327. Disclosure: The author reports no disclosures.
Reply to Yoshii et al. and De Carvalho 10 February 2009
Mario Sabatelli, Catholic University of Sacred Heart Neurology Department "A: Gemelli", Largo Gemelli, 8, 00168 Rome, Italy, Marco Luigetti, Amelia Conte and Marcella Zollino Send Correspondence to journal: Re: Reply to Yoshii et al. and De Carvalho msabatelli{at}rm.unicatt.it Mario Sabatelli, et al.	We appreciate the comments made by Yoshii et al and Dr. De Carvalho. Yoshii et al. discuss, in addition to the unique distribution by age and gender and the longer survival, that a striking feature of ALS patients with predominant Upper Motor Neuron (p-UMN) form is the stereotypical topographic distribution of UMN and lower motor neurons (LMN) signs. We agree that this phenotype, with bulbar-spinal spasticity and LMN signs starting in distal upper limb muscles, is similar to some forms of juvenile ALS with clear mendelian inheritance. As they mention, ALS2-related syndrome includes this phenotype. In addition, a similar clinical pattern is observed in some patients with ALS4, due to SETX mutations [8] and in ALS5, the most frequent form of Juvenile ALS. [9] Furthermore, heterozygous missense mutations in the BSCL2 gene cause different forms of autosomal-dominant disorders of motoneurons, including distal SMA V and Silver Syndrome. [10,11] The latter condition is characterized by spastic paraparesis, distal muscle weakness and wasting of the upper and sometimes lower limbs. When pyramidal tracts are severely involved in ALS, degeneration of lower motor neurons usually starts in the cervical spinal cord. The significance of this peculiar pattern of spread of the degenerative process is unknown. Its occurrence in both familial and sporadic forms of ALS suggests that different factors may trigger the same final mechanisms, and further supports the hypothesis that genetic factors play a pivotal role in sporadic ALS. We also thank Dr. de Carvalho for his comments. It is clear from our data that predominant Upper Motor Neuron (p-UMN) phenotype is associated with longer survival in both young-adult and adult. We did not include this in the discussion because our objective was to delineate the clinical aspects and natural history of young-adult ALS. There is ongoing research on prognostic significance of p-UMN phenotype in our center. Dr. de Carvalho mentions that his paper on sporadic juvenile form of ALS (JALS) should have been cited. [7] In this article, three patients with JALS and a review of 24 other cases from the literature are described. JALS is a genetic and regional disorder with involvement of several genes [12] and we do not believe that grouping these cases as a single entity is the best approach for understanding this rare condition. We decided to mention well documented cases when referring to JALS. [6] Concerning the symmetry of clinical presentation, we state that in the fully developed phase: "Muscular atrophy was obvious but confined to the upper limbs, bilaterally, with a slight degree of asymmetry and it was more pronounced in distal than in proximal muscles". References 8. Chen YZ, Bennett CL, Huynh HM et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004;74:1128-1135. 9. Hentati A, Ouahchi, K, Pericak-Vance M. A et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998;2:55-60. 10. Windpassinger C, Auer-Grumbach M, Irobi J, et al. Heterozygous missense mutations in the BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 2004;36:271;V276. 11. Irobi J, Van den Bergh P, Merlini P, et al. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain 2004;127:2124;V2130. 12. Bonduelle M. Amyotrophic lateral sclerosis. In: Winken PJ, Bruyn GW, editors in collaboration with J. M. B. V. De Jong. Handbook of Clinical Neurology. Amsterdam: North-Holland Publishing Company; 1975. Vol. 22 p. 281-338. Disclosure: The authors report no disclosures.