Juvenile Amyotrophic Lateral Sclerosis

Introduction

The motor neuron diseases (MNDs) constitute a debilitating range of disorders that cause variable disability and affect all ages from neonates to the elderly. The best known, most aggressive, and most common MND in adults is amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). In rare cases it can affect children and young (<25 years) adults, in which case it may be designated juvenile ALS (jALS). Juvenile ALS overlaps with classical ALS but has significant differences. By comparing and contrasting the two we may be able to understand the biology of motor neuron degeneration and the role of perturbations in developmental events in the genesis of motor neuron disease. It is likely that the juvenile instances of ALS will offer intriguing genetic insights into motor neuron degeneration with considerable relevance to ALS in general.

Critically, both jALS and typical ALS involve the same general populations of motor neurons, including primarily those that reside in the spinal cord and brainstem to innervate muscle (“lower motor neurons”) and those in the frontal regions that descend to influence the lower motor neurons. The latter project to the spinal motor neurons via both mono- and polysynaptic pathways, predominantly in the cortico-bulbar and cortico-spinal tracts. That this selective set of neurons is comparably affected in both jALS and ALS strongly suggests that these different diseases share some common molecular mechanisms. An understanding of even the rarest of motor neuron diseases may well yield insight into more common forms. In this review we will draw attention to the expanding field of jALS with an emphasis on genetic highlights potentially of broad relevance to all types of ALS.

Nosology of Motor Neuron Diseases

A number of different terms are commonly used to describe the progressive, degenerative motor neuron diseases. Classification under these headings is largely dependent on the predominant and earliest noted clinical feature. Lower motor neuron (LMN) syndromic terms are progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), and distal hereditary motor neuropathy (dHMN) or distal SMA. Upper motor neuron (UMN) syndromes include primary lateral sclerosis (PLS) and hereditary spastic paraparesis (HSP). However, there is often a great deal of phenotypic overlap between the diseases that these terms are used to describe, rendering them confusing if not frankly redundant. In many cases mutations in a single gene can give rise to one or another of the canonical syndromes.

The clinical manifestations of LMN and UMN failure are quite distinct. In LMN degeneration, there is weakness, flaccid dysarthria (laxity of tongue and orolabial muscles), and flaccid atrophy of the limbs, usually with fasciculations, and often accompanied by premonitory cramps. In UMN degeneration, there is weakness, limb stiffness, spastic dysarthria (tightness of tongue and lip movement, like eating a hot potato), and emotional lability (pseudobulbar affect). PMA has a clinical and temporal course that mimics ALS but without UMN features. Although the course is generally slowly progressive, there are numerous important exceptions to this rule, and some patients may go on to develop UMN features, fulfilling the criteria for a diagnosis of ALS. In dHMN, by contrast with PMA, weakness and atrophy are more obviously peripheral; these features may overlap with axonal forms of Charcot-Marie-Tooth disease (CMT). In dHMN, juvenile onset is common. In addition, atypical features are often present, such as sensory and (infrequently) UMN features. For this reason, it is reasonable to consider some forms of dHMN as atypical ALS syndromes rather than pure dHMN.

As reviewed in detail elsewhere in this volume, SMA is a degenerative disorder selectively affecting LMNs. There is a striking disparity in the clinical severity in these cases. In some, the onset is apparently intrauterine; there are joint contractures at birth (arthrogryposis) attesting to restriction of limb movement before birth. In others, the disorder declares itself within the first few postnatal days or weeks, heralded by severe newborn weakness, hypotonia, respiratory insufficiency and difficulty crying and sucking. In these aggressive newborn cases (Werdnig-Hoffman disease) tongue fasciculations are common, and there is tremulousness of the limbs, presumably also reflecting abnormal firing of motor neurons. In still other cases, the clinical manifestations are not well-defined until late teen or early adult years. SMA is the commonest genetic cause of neonatal mortality and is caused by loss of function of the survival motor neuron 1 gene ( SMN1 ). The clinical severity is dictated by the number of copies of the SMN2 gene (see Chapter 8 ). Moreover, it is now appreciated that there are multiple genes whose mutations cause the phenotype of SMA.

Juvenile ponto-bulbar palsies include Brown-Vialetto-Van Laere (BVVL) syndrome and Madras Motor Neuron Disease (MMND). The former is often a disorder of early childhood, while the latter may not show onset until the early teens. The central element in both disorders is bulbar LMN degeneration affecting speech and swallowing. However, MMND can entail nonmotor aspects, such as deafness and visual dysfunction. Indeed, there are cases of MMND in which deafness is the first manifestation. Because these disorders are very rare, it is difficult to find large sets of pedigrees from which one can confidently garner insight into the mode of transmission of the affected genes. Both probably have recessively inherited forms, and there are some pedigrees of MMND that suggest inheritance may be dominant.

PLS is essentially ALS without LMN features. The course of PLS varies. While in some cases the disease evolves slowly, in others it proves to be quite disabling with bulbar involvement and a time course resembling that of ALS. It is not uncommon for cases that begin insidiously with a PLS phenotype to develop LMN features.

The HSPs constitute a huge and growing group of diseases (reviewed by Fink ). Defects in multiple genes have been defined as causing HSP; in many instances, the genetic locus but not the specific defect has been identified. In some classifications, these are designed as SPG ( S pastic P araple G ia) and numbered in order of discovery. Multiple inheritance patterns are seen. HSP may be autosomal dominant, recessive, X-linked or, in at least one case, mitochondrially inherited. Clinically, patients develop mainly lower limb spasticity and weakness as well as dorsal column impairment causing reduced vibratory sensation. Weakness is usually symmetric. Urinary urgency is common.

HSP phenotypes vary considerably from essentially “uncomplicated” forms with spastic paraparesis alone to “complicated” variants associated with involvement of other central and/or peripheral parts of the nervous system and, rarely, systemic manifestations. Clinical deterioration in HSP is variable but usually very slow, though often nonuniform. In many patients the upper limbs remain uninvolved and lifespan is not affected. Disease may reach a plateau phase after 5–10 years of progression. Pathological data, though limited, have shown distal axonopathy in the corticospinal tract and the gracile fascicle (worst in the cervical cord).

Molecular Classification of jALS—Syndromes of Juvenile ALS

With these general points as background, we have compiled a list of disorders that in our view arise as differential considerations in the category of jALS ( Table 9.1 ). This classification is intended to be inclusive, spanning some disorders that, as described previously, are not always considered as jALS. We discuss the major entities on this list in the following sections. We define jALS as any progressive motor neuron disease affecting both upper and lower motor neurons with onset at age 25 years or less. There are many syndromes fitting this description, all of which are extremely rare. Unlike typical adult-onset ALS, jALS is often very slowly progressive, nonfatal, and may affect nonmotor systems. Inheritance is often autosomal recessive rather than dominant, the more typical pattern in adult-onset familial ALS (fALS). Disease is often manifested in closed populations in which consanguineous marriages are the norm. In recent years, detailed family trees and genetic analyses of blood DNA extraction have yielded many new genes linked to juvenile forms of motor neuron disease. Because of the diversity of forms of jALS, the organization of any review is necessarily somewhat arbitrary. We have elected to consider four categories of disorders: (1) ALS overlaps; (2) lower motor neuron predominant; (3) upper motor neuron predominant; and (4) miscellaneous forms of jALS.

Table 9.1

Molecular Genetics of Selected Types of Juvenile ALS

Disease	Gene	Locus	Protein	Inheri-Tance	Non-jALS Aspect	Gene/Protein Function
ALS Overlap Disorders
ALS2	ALS2	2q33.1	alsin	AR		Guanine nucleotide exchange, endosomal trafficking
ALS4	SETX	9q34.13	senataxin	AD		DNA/RNA helicase
ALS5	SPG11	15q15.1	spatacsin	AR	HSP	Transmembrane protein; role in axon maintenance
ALS6	FUS	16p11.2	fused in sarcoma	AD	ALS	DNA/RNA binding protein
ALS16	SIGMAR1	9p13.3	opioid sigmoid receptor	AR		Non-opioid receptor, ER chaperone
SPG18	ERLIN2	8p11.22	ER lipid raft protein 2	AR	kyphoscoliosis, saccadic eye movements	Functions in protein degradation in the endoplasmic reticulum
jALS		6p25, 21q22	unknown	AR	ptosis, gynecomastia
BVVL1 *	C2orf54]	20p13	SLC52A3 riboflavin transporter	AR	deafness	Transports riboflavin, the central component of cofactors FMN and FAD
BVVL2	GPR172A	8q24	SLC52A2 riboflavin transporter	AR	deafness, optic atrophy	Transports riboflavin, the central component of cofactors FMN and FAD
BVVL	GPR172B	17p13.2	SLC52A1 riboflavin transporter	AD		Transports riboflavin, the central component of cofactors FMN and FAD
BVVL	UBQLN1	9q21.32	ubiquilin 1	AD	deafness	Targeting ubiquitinated proteins for degradation
Madras MND			unknown	AR, S	deafness, optic atrophy
Lower Motor Neuron Predominant
dHMN	BSCL2 **	11q13	seipin	AD	jALS – upper limb	ER *** glycoprotein modulates unfolded protein response
dHMN	DCTN1	2p13	dynactin 1	AD		Retrograde axonal transport
dHMN	HSPB1	7q11.23	HSP27	AD/AR
dHMN		7q34-36	unknown	AD
dHMN		4q34-35	unknown	AD	neuropathy
dHMN (Jerash)		9p21,1-12	unknown	AR
Upper Motor Neuron Predominant
SPG3A	ATL1	14q11-q21	atlastin	AD	HSP-like	Enhances ER membrane fusion, interacts with spastin, REEP1, NIPA1
SPG4	SPAST	2p22.3	spastin	AD	HSP-like	Microtubule severing
SPG20	Spartin	13q	spartin	AR	HSP-like	Endosomal trafficking, microtubule binding dynamics
SPG39	PNPLA6	19p13.2	neuropathy target esterase	AR	HSP-like	Deacetylates phosphatidylcholine, may reduce organophosphate toxicity
SPOAN ****		11q13	gene unknown	AR	HSP-like
SPG57	TFG	3q12	TRK-fused gene	AR	HSP/HSAN *****	Oncogene, with role in RNA sensing and NF-kappaB pathway
SPG31	REEP1	2p11.2	Receptor expression-enhancing protein 1 (REEP1)	AD	HSP-like	Functions in ER and in vesicle transport

AR: autosomal recessive

AD: autosomal dominant

S: sporadic

* Brown-Vialeto-van Laere

** Berardinelli-Seip Congenital Lipodystrophy

*** endoplasmic reticulum

**** spastic paraplegia, optic atrophy, neuropathy

***** hereditary sensory-motor autonomic neuropathy

Discussion of Table 9.1

ALS Overlap Disorders

ALS2 (Alsin)

ALS2 is a rare, recessively inherited, juvenile-onset form of ALS. It is predominantly a UMN syndrome characterized by slowly progressive spasticity beginning in the lower limbs, with gradual extension upwards to involve the upper limbs and bulbar musculature. Truncation mutations in the ALS2 gene (coding for alsin) were found in kindreds from Tunisia and Kuwait, and also in a Saudi Arabian family with juvenile PLS. Mutations in alsin have also been found in several families with a syndrome described as infantile-onset ascending hereditary spastic paraplegia (IAHSP). Most mutations generate truncated alsin products, which are unstable leading to loss of function. Homozygous missense mutations have also been described, in association with alsin protein mislocalization, leading to loss of function. There are no published reports of the neuropathology of ALS2 patients.

The alsin gene is ubiquitously expressed in the CNS (especially cerebellum) and periphery (especially kidney). Alsin appears to protect cultured neurons from mutant SOD1-mediated toxicity ; its overexpression promotes hippocampal neurite outgrowth through Rac1 activation. Alsin may also have a role in preventing glutamate mediated excitotoxicity by appropriate expression of the Ca ² ⁺ impermeable Glur2 subunit of AMPA receptors.

The best characterized properties of alsin relate to its functions in endosomal dynamics. Present in the cytoplasm, alsin is relocalized to endosomes by Rac1. Alsin then acts as a guanine-nucleotide exchange factor (GEF) to activate the GTPase Rab5. Rab5 is important for endocytosis, endosome fusion and endosomal trafficking. Alsin knockout mice have relatively subtle motor phenotypes and pathological changes are limited to mild corticospinal tract degeneration, suggesting that ALS2 may be a distal axonopathy. However, in vitro studies of alsin null neurons and fibroblasts confirm reduced endosomal trafficking and altered endosomal fusion. Furthermore, the rare missense mutations of alsin appear to act through loss of function due to impairment of Rac1-mediated relocalization to endosomes.

ALS4 (Senataxin)

ALS4 is a rare, nonfatal, autosomal dominant, juvenile-onset dHMN characterized by limb weakness, severe muscle wasting and pyramidal tract signs including brisk reflexes and extensor plantar responses. Bulbar and respiratory muscles are spared and lifespan is unaffected. The mean age of onset is 17 years. Symptoms begin with difficulty walking followed by weakness and wasting of intrinsic hand and foot muscles. By the fourth to fifth decade, patients display significant proximal weakness and are often wheelchair-bound. By the sixth decade, many lose hand function entirely. Sensation remains normal both clinically and electrophysiologically, although pathological studies have shown dorsal column degeneration in addition to corticospinal tract degeneration and anterior horn cell loss.

ALS4 was first characterized in four kindreds from America and Europe and linked to a locus on Chr 9q. Dominant missense mutations in the SETX gene encoding senataxin were subsequently found. In all, as of 2013 only seven mutations in senataxin affecting 64 individuals were listed on the ALS Online Genetics Database (ALSoD). These affect the N-terminus and helicase domain. A dominant SETX mutation has also been found in a family with dominantly transmitted proximal SMA (ADSMA). Interestingly, mutations of SETX cause ataxia-oculomotor apraxia 2 (AOA2), although in these cases the mutations are recessive and mostly truncations. A toxic gain of senataxin function may be responsible for ALS4, while loss of function may lead to AOA2.

The full range of functions of senataxin remains to be determined. It seems clear that it has a putative DNA/RNA helicase domain and demonstrates punctate expression in the nucleus and diffuse expression in the cytoplasm. Senataxin is important in preventing oxidative damage to DNA, interacts with a variety of RNA processing proteins (including RNA polymerase II and SMN) and influences gene transcription and mRNA splicing. Senataxin also shows homology to another putative DNA/RNA helicase, immunoglobulin μ-binding protein 2 (IGHMBP2). Notably, recessive (probably loss of function) mutations of IGHMBP2 cause a childhood onset LMN disease, spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Senataxin knockout mice have no motor phenotype but the observation that male animals are sterile and females are subfertile led to detailed studies demonstrating critical roles for senataxin in crossing over in meiosis, meiotic sex chromosome inactivation, and DNA damage response.

In spite of this research on loss of senataxin function, which is clearly relevant to AOA2, the mechanisms by which dominant mutations cause ALS4 remain relatively unexplored. In vitro studies demonstrate a role for senataxin in neuritogenesis through fibroblast growth factor 8 and suggest that the dominant mutants lack this ability. Thus, haploinsufficiency is a possible mechanism of disease in ALS4.

Finally, caution should be taken in interpreting SETX sequencing results. Several variants described in the literature as ALS4-causing mutations may actually be benign polymorphisms, although it remains possible that they may contribute to disease risk or phenotype without being completely penetrant.

ALS5/SPG11 (Spatacsin)

ALS5, on chromosome 15q, was originally described in several kindreds from Tunisia and Germany with autosomal recessive jALS. Families were linked to chromosome 15q15.1-21.1. Patients develop progressive gait disturbance, presenting with mixed UMN and LMN features between 8 and 18 years of age. Dysarthria begins after 3 to 4 years and survival is generally 10–25 years from symptom onset. In parallel studies, a form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC), designated SPG11, was reported to be caused by mutations in a novel gene, labelled spatacsin. This is a transmembrane protein that is phosphorylated after DNA damage; its function is not well understood. Of interest, Orlacchio et al. collected a series of 25 families (from Italy, Japan, Turkey, Canada) with recessively inherited jALS; 10 of the 25 kindreds were found to have mutations in spatacsin . While we do not know if the gene defect in the original ALS5 families has been confirmed to be in spatacsin , the general premise now accepted is that the ALS5 gene is indeed spatacsin .

ALS6 (Fused in Sarcoma/Translocated in Liposarcoma)

This form of ALS most commonly arises in adults with a typical, if somewhat aggressive, phenotype. However, it is now well documented to arise in individuals in the second decade, usually with a devastatingly rapid course. These cases are all caused by mutations in the gene encoding FUS (fused in sarcoma), a multifunctional RNA- and DNA-binding protein of 525 amino acids. FUS is normally located almost exclusively within the nucleus but is observed to exit to the cytosol after exposure to some cellular stresses (e.g. hyperosmolar shock). Mutant FUS is observed to mislocalize to the cytosol where it sometimes participates in forming aggregates. Rapidly progressive jALS has been associated with several different FUS gene mutations; among the most aggressive is a particular dominant missense variant that substitutes lysine for proline at codon 525, thereby disrupting the nuclear localization signal. At autopsy these cases are associated with distinctive basophilic intranuclear aggregates.

ALS16 (Sigma-1 Intracellular Receptor) and SPG18 (ERLIN2)

A homozygous missense mutation (E102Q) in SIGMAR1 (encoding sigma nonopioid intracellular receptor 1, Sig-1 R) was comparatively recently reported in a consanguineous Saudi family with autosomal recessively inherited jALS. The phenotype was slowly progressive, with predominantly UMN involvement.

Sig-1 R regulates K ⁺ channels and is involved in Ca ²⁺ signaling through IP3R. It is a receptor for a variety of ligands including steroids, psychostimulants, and haloperidol. It also has chaperone activities in the ER, implicating the unfolded protein response in neurodegeneration. In vitro studies showed that the E102Q mutation abrogates the ability of SigR1 to suppress apoptosis induced by ER stress. The E102Q mutation occurs in a predicted transmembrane domain and subcellular fractionation suggests that the mutation causes a shift to lower density membrane fractions where mutant protein forms detergent-resistant complexes.

A role for SigR1 in sporadic ALS has also been suggested by pathological studies showing altered distribution of SigR1 at C-boutons (excitatory postsynaptic densities at spinal cord motor neurons) and cytoplasmic accumulation of SigR1.

The homozygous E102Q mutation is the only clearly pathogenic mutation yet described. Heterozygous 3′ untranslated region (UTR) variants described in familial ALS-FTLD have been identified but it remains unclear whether these are actually benign polymorphisms or whether they do contribute to disease risk. No animal studies of these mutations have yet been conducted, but a recent study in mice showed that the native Sig-1 R protein is located exclusively in motor neurons, and that knockout causes motility problems. Furthermore, the Sig-1 R agonist PRE-084 has recently been shown to be protective in both SOD1-G93A and wobbler models of ALS, supporting a loss of function as the mechanism by which Sig-1 R mutation may cause disease.

In the context of ER stress it is worth noting the recent discovery of recessive mutations in ERLIN2, an endoplasmic reticulum protein that is associated with lipid rafts, in an inbred family with juvenile PLS. Patients were normal at birth but developed impaired crawling at 8 months of age, toe walking at two years with progressively impaired mobility such that they were bedridden by just 15 years of age. In addition to severe generalized spasticity by end stage, patients also developed severe dysarthria and pseudobulbar palsy, skeletal deformities including kyphoscoliosis, saccadic eye movements, and moderate distal limb wasting. Brain PET scan showed hypometabolism in the temporal and parietal lobes. Erlin2 is similar to Sig-1 R in that it is a component of ER lipid rafts. Splice junction mutation of the ERLIN2 gene results in nonsense-mediated decay of aberrantly spliced transcripts causing a loss of function. It will be interesting to determine whether Erlin2 and Sig-1 R interact and how they contribute to distinct clinical phenotypes.

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