Case Reports in Genetics

Case Reports in Genetics / 2014 / Article

Case Report | Open Access

Volume 2014 |Article ID 691515 |

Filipa Flor-de-Lima, Mafalda Sampaio, Nahid Nahavandi, Susana Fernandes, Miguel Leão, "Alsin Related Disorders: Literature Review and Case Study with Novel Mutations", Case Reports in Genetics, vol. 2014, Article ID 691515, 5 pages, 2014.

Alsin Related Disorders: Literature Review and Case Study with Novel Mutations

Academic Editor: Patrick Morrison
Received31 May 2014
Revised20 Aug 2014
Accepted01 Sep 2014
Published14 Sep 2014


Mutations in the ALS2 gene cause three distinct disorders: infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and autosomal recessive juvenile amyotrophic lateral sclerosis. We present a review of the literature and the case of a 16-year-old boy who is, to the best of our knowledge, the first Portuguese case with infantile ascending hereditary spastic paraplegia. Clinical investigations included sequencing analysis of the ALS2 gene, which revealed a heterozygous mutation in exon 5 (c.1425_1428del p.G477Af19) and a heterozygous and previously unreported variant in exon 3 (c.145G>A p.G49R). We also examined 42 reported cases on the clinical characteristics and neurophysiological and imaging studies of patients with known ALS2 gene mutations sourced from PubMed. This showed that an overlap of phenotypic manifestations can exist in patients with infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and juvenile amyotrophic lateral sclerosis.

1. Introduction

Three apparently distinct disorders involving retrograde degeneration of the upper motor neurons of the pyramidal tracts seem to be caused by mutations in the ALS2 gene, which provides instructions for making a protein called Alsin. They comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) (OMIM number 607225), to juvenile forms without lower motor neuron involvement, namely, juvenile primary lateral sclerosis (JJPLS) (OMIM number 606353), and to forms with lower motor neuron involvement, namely, autosomal recessive juvenile amyotrophic lateral sclerosis (JALS) (OMIM number 205100) [1, 2]. There is no available data on the prevalence of ALS2 related disorders. However, they are probably currently underdiagnosed, even if they have been described in individuals from a variety of ethnic backgrounds, mainly from the Mediterranean [1].

All the patients are homozygous or heterozygous compounds for ALS2 mutations [1]. To date, a total of 45 patients with known mutations in the ALS2 gene have been described, but the phenotype-genotype correlation remains unclear [2]. In the present study, we describe the clinical and genetic features of a 16-year-old boy with IAHSP from Northern Portugal (Table 1).

PatientExon/intronMutationPredicted proteinPhenotypic classificationReferences

1Intron 24c.3836+1G>Tp.k1234fs*3IAHSP Racis et al., 2014 [5]

2Intron 9c.2000-2A>Tp.E724fs*32IAHSPHerzfeld et al., 2009 [6]

3Exon 9c.1825_1826ins5p.E609fs*9IAHSP Sztriha et al., 2008 [7]
4Exon 13c.2529G>Tp.G1177*IAHSP

5, 6Exon 10c.2143C>Tp.Q715*IAHSP Verschuuren-Bemelmans et al., 2008 [8]

7, 8Exon 4c.467G>Ap.C156YIAHSP Eymard-Pierre et al., 2006 [9]

9, 10Exon 18c.2992C>Tp.R998*IAHSPDevon et al., 2003 [10]

11Exon 32c.4844delTp.I331fs335IAHSPGros-Louis et al., 2003 [11]

12–17Exon 4c.1130delATp.I331fs335IAHSP Eymard-Pierre et al., 2002 [12]
Exon 13c.2660delATp.N845fs858IAHSP
Exon 6c.1471_1480del10p.V491Gfs*3IAHSP
Exon 22c.3742delAp.M1206*IAHSP

18–20Exon 5C.1548delAGp.T475Tfs*70IAHSPHadano et al., 2001 [4]

21Exon 5
Exon 3
IAHSPOur study

22-23Exon 4
Exon 14
Luigetti et al., 2013 [13]

24-25Exon 22c.3565delGp.V1189WfsX19JALSShirakawa et al., 2009 [2]

26Exon 4c.553delAp.T185LfsX5JALSKress et al., 2005 [14]

27–38Exon 3c.138delAp.A46AfsX5JALSHadano et al., 2001 [4]

39–41Intron 17c.2980-A>Gp.T993fs*7JPLSMintchev et al., 2009 [15]

42Exon 6c.1619Gp.G540EJPLSPanzeri et al., 2006 [16]

2. Case Report

The patient was born after a twin pregnancy from nonconsanguineous parents and the pregnancy included maternal hemorrhage in the second trimester. Delivery was at the 36th week of gestation by Cesarean section. The twins were dizygotic twins and the patient’s twin sibling is healthy. His 42-year-old mother is healthy and his father died at the age of 35 after a car accident, without any signs of a neurological disorder. The boy acquired cephalic control at three months and started to sit unaided at six months, crawl at nine months, and walk with support at 10 to 11 months. Stiffness of the lower limbs and tiptoeing with hyperactive deep tendon reflexes were noticed at the age of three and scissoring gait started during his fourth year. He was never able to walk without support and underwent Achilles tenotomy at the ages of three and five. An ascending progression of motor difficulties was observed, with spasticity becoming evident in the upper extremities after the age of six. Muscle atrophy in the lower limbs was evident after the age of seven and he was wheelchair bound at the age of eight. Sphincter incontinence started at the same time and he developed supranuclear bulbar palsy, with progressive dysarthria. MRI, electromyography, and nerve conduction studies at that age were normal. Anarthria was evident at the age of 13. At the age of 14, there was clinical worsening and since then he has had bilateral limitation of horizontal eye movements, dysphagia when drinking liquids, chewing difficulties, severe drooling, and paroxysms of laughter. Cognitive function is still normal at the age of 16.

3. Material and Methods

DNA was extracted from a peripheral blood sample from the patient, his mother, and twin brother. All 34 exons of the ALS2 gene were analysed by PCR and sequencing of both DNA strands of the entire coding region was carried out, including the highly conserved exon-intron splice junctions.

We also reviewed all cases of ALS2 related disorders with known ALS2 gene mutations and detailed clinical, neurophysiological, and imaging data that have so far been reported in PubMed. Continuous variables with asymmetric distribution are described by medians (minimum to maximum) and categorical variables are described by absolute and relative frequencies. To compare the three phenotypes (IAHSP, JALS, and JPLS) we used the Kruskal-Wallis test if the variables were continuous and the Monte Carlo test if they were categorical. The statistical analysis was performed using SPSS v.20 (IBM, USA) and values of less than 0.05 were considered significantly different.

4. Results and Discussion

Our patient displays a clinical picture that is highly suggestive of ALS2 related disorder. This case study presents evidence of previously unreported heterozygous variants in exon 5 (c.1425_1428del p.G477Af19) and exon 3 (c.145G>A p.G49R).

To date, case studies of 45 patients with ALS mutations have been reported. Four patients with JALS were excluded because a detailed clinical description was not available [3]. The clinical characteristics and neurophysiological and imaging studies of the remaining 41 cases, plus our case study, are summarized in Table 2. Of these, 21 (50%) of the patients were classified as having an IAHSP phenotype, 17 (40.5%) had a JALS phenotype, and four (9.5%) had a JPLS phenotype. Median age at onset of walking loss, upper limb involvement, speech impairment, and becoming wheelchair bound was similar between the three groups.

PatientAgeOriginMotor development by 1 yearAge at onsetLoss of walkingUpper limb involvementBulbar involvementSpeech impairmentOcular movementsWheelchair boundEMGEvoked potentialsBrain imagingPhenotypic classificationReferences

117 yItalyAb12 moNA8 y8 y Disarthria at 8 y, Anarthria at 11 y8 yAbSSEP abAbIAHSPRacis et al., 2014 [5]

27 yGermanyAb18 mo<7 y<7 y7 yN7 yAbIAHSPHerzfeld et al., 2009 [6]

311 yHungaryAb10 moNA2 y5 yNoN11 yNMotor abNIAHSP Sztriha et al., 2008 [7]
46 yHungaryAb<1 yNANo5 yNoN5 yNIAHSP

513 yThe NetherlandsAb8 moNA3 y5 yAnarthria at 13 yN13 yNMEP UnobtainableNIAHSP Verschuuren-Bemelmans et al., 2008 [8]
68 yThe NetherlandsGrossly N18 moNAYes4 yNoNNoNMEP UnobtainableNIAHSP

722 yTurkeyAb1 y12 y12 y16 yNo12 yIAHSP Eymard-Pierre et al., 2006 [9]
820 yTurkeyAb1 y10 y12 yNo10 yNMotor abAbIAHSP

99 yBukhari JewishN1-2 yNA2 y3 yDysarthria at 9 yNoIAHSP Devon et al., 2003 [10]
106 yBukhari JewishN14 mo6 y6 y6 yDysarthria at 6 yNoNNIAHSP

1112 yPakistanAb18 mo12 y<12 yAnarthria at 12 y12 yIAHSPGros-Louis et al., 2003 [11]

1236 yAlgeria1 yNA<7 y13 yDysarthria at 13 yNNMEP and SSEP abnormalAbIAHSP

Eymard-Pierre et al., 2002 [12]
1331 yAlgeria1 yNA<7 y13 yDysarthria at 13 yNNMEP and SSEP abnormalIAHSP
1424 yAlgeria1 yNA<7 y13 yDysarthria at 13 yNNMEP and SSEP abnormalIAHSP
1518 yFrance1.5 y4 y6 y8 yDysarthria at 4 y, anarthria at 12 yAbNMEP and SSEP abnormalAbIAHSP
1623 yItaly1.4 y5 y10 y12 yDysarthria at 10 y, anarthria at 16 yAbNMEP and SSEP abnormalAbIAHSP
1720 yItaly1.5 y4 y9 y13 yDysarthria at 11 y, anarthria at 18 yAbNMEP and SSEP abnormalAbIAHSP

1814 yKuwaitN14 mo2 y9 y4 yDysarthria at 4 y, anarthria at 14 yNNAbIAHSP Hadano et al., 2001 [4]
196 yKuwaitAb11 moNA5 yDysarthria at 5 y,NNoAbIAHSP
202 yKuwaitAb9 moNAIAHSP

2116 yPortugalN3 yNA6 y8 yDysarthria at 8 y, anarthria at 13 yAb8 yNNIAHSPOur study

2227 yItalyN3 yDysarthria at 7 y, anarthria at 14 yAbSSEP NNJALS Luigetti et al., 2013 [13]
2321 yItalyN6 yAbSSEP NNJALS

2432 yJapanN13 moNo11 yDysarthria at 11 y, anarthria at 14 yNoAbNJALS Shirakawa et al., 2009 [2]
2523 yJapanN3 yNo DysarthriaNoJALS

2632 yTurkeyAb22 mo16 y12 y15 y18 y16 yAbMotor ab, SSEP NJALSKress et al., 2005 [14]

2760 yTunisiaN10 y10 yNMotor NJALS Hadano et al., 2001 [4]
2836 yTunisiaN6.5 y6.5 yNJALS
2927 yTunisiaN3.5 yYesNMotor N, SSEP abJALS
3022 yTunisiaN6.5 y6.5 yNMotor NJALS
3121 yTunisiaN9 y9 yNJALS
3214 yTunisiaN6.5 y6.5 yNJALS
3323 yTunisiaN6.5 y6.5 yNMotor NJALS
3428 yTunisiaN3.5 yYesNJALS
3532 yTunisiaN7.5 yYesNMotor NJALS
3622 yTunisiaN6.5 yYesNJALS
3721 yTunisiaN10 yYesNMotor N, SSEP abJALS
387 yTunisiaN6 yYesNJALS

3955 yCyprusN2 y50 yYes3 yAb50 yJPLS Mintchev et al., 2009 [15]
4042 yCyprusN2 y2 yYes2 yAb2 ySSEP NNJPLS
4116 yCyprusN2 yNoYes2 yAbNoAbJPLS

4234 yItalyN2 y19 y2 y6 yDysarthria at 6 y, anarthria at 20 yAb34 yAbMotor abNJPLSPanzeri et al., 2006 [16]

EMG: electromyography; N: normal; Ab: abnormal; NA: not achieved; y: years; mo: months; MEP: motor evoked potentials; SSEP: somatosensory evoked potentials.

The heterozygous variant in exon 5 (c.1425_1428del p.G477Af19) creates a shift in the reading frame, starting at codon 477. The new reading frame ends in a stop codon 18 positions downstream, which is very likely to result in truncated protein or loss of protein production. Therefore, it is very likely to be a disease causing mutation. A small deletion in this region (c.1427_1428delAG), which also causes a frameshift, has previously been described as disease causing for ALS2 [4]. The other unreported heterozygous variant was found in exon 3 (c.145G>A p.G49R), which is located in a moderately conserved amino acid, with moderate physiochemical differences between the amino acids glycine and arginine. Polyphen-2, SIFT, and MutationTaster predict that this variant is probably damaging. This variant in exon 3 was also found in our patient’s twin brother and their mother, who were both healthy. It was impossible to test his father because he was dead.

Despite the limited number of patients reported in the literature with known ALS2 mutations and considering the bias related to the age, the majority of clinical characteristics were similar between both groups. Because all the families reported to date have had different ALS2 mutations, it is impossible to draw any genotype-phenotype correlation.

5. Conclusions

Despite the limited information about clinical characteristics, patients with IAHSP, JALS, and JPLS may present with different phenotypes that overlap.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


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Copyright © 2014 Filipa Flor-de-Lima et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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