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Rare Forms of Autosomal Recessive Neurodegenerative Ataxia

Michel Koenig

here has been a recent explosion in knowledge regarding the genetic basis of several autosomal recessivetaxias. This article summarizes current information regarding rare forms of recessive ataxias. Friedreich’s ataxiand ataxia telangiectasia are dealt with in other articles in this issue. The rarer recessive ataxias can be clinicallylassified as sensory and spinocerbellar ataxias, cerebellar ataxia with sensory-motor polyneuropathy, and purelyerebellar ataxias. Examples of the first category include ataxia with isolated vitamin E deficiency, abetalipopro-einemia, Refsum’s disease, infantile-onset spinocerebellar ataxia, and ataxia with blindness and deafness.xamples of ataxia with sensory-motor polyneuropathy include ataxia with oculomotor apraxia 1 and 2 andpinocerebellar ataxia with neuropathy 1. Examples of purely cerebellar ataxia include autosomal recessivepastic ataxia of Charlevoix-Saguenay and ataxia with hypogonadotropic hypogonadism. This review summarizeshe clinical and genetic features of these entities and concludes that the pathogenic basis of such ataxias at thisime appear to involve two broad types of processes: free-radical injury and defects of DNA single- or double-trand break repair.

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UTOSOMAL RECESSIVE neurodegenera-tive ataxias are classified according to the

ajor site of degeneration, which can be the cer-bellum or the spinal cord. In the latter case,egeneration of the posterior columns and ofpinocerebellar tracts leads to sensory (propriocep-ive) and cerebellar ataxia. A third group of disor-ers, recently identified, involves concurrent cere-ellar degeneration and sensorimotor peripheraleuropathy, resulting in sensory and cerebellartaxia associated with neuromuscular weakness.he first group is dominated by ataxia-telangiecta-ia (A-T), wherein cerebellar atrophy is associatedith immune deficiency and susceptibility to ma-

ignancies. Other disorders in the first group arepastic ataxia of the Charlevoix-Saguenay regionARSACS) and cerebellar ataxia with hypogona-otrophic hypogonadism. The second group isominated by Friedreich’s ataxia (FA), a disorderecognized since the nineteenth century. Rareorms of spinal cord ataxias include the inheriteditamin E deficiencies (isolated vitamin E defi-iency [AVED] and abetalipoproteinemia [ABL]),efsum’s disease (RD), infantile-onset spinocere-ellar ataxia (IOSCA), and ataxia plus blindnessnd deafness (SCABD). The third group, disordersf cerebellar atrophy with sensorimotor neuropa-hy, comprises only very recently identified condi-ions, including ataxia plus oculomotor apraxia,orms 1 and 2 (AOA1 and AOA2) and spinocere-ellar ataxia plus neuropathy (SCAN1). The twoajor recessive ataxias, FA and A-T, are discussed

n other articles in this issue. This overview fo-uses on the delineation of the rare forms of reces-

ive ataxias, which recently has been made possi-

eminars in Pediatric Neurology, Vol 10, No 3 (September), 2003: pp 183

le thanks to the development of positional cloningtrategies based on homozygosity mapping of con-anguineous families and on the development ofhe human genome project.

SENSORY AND SPINOCEREBELLAR ATAXIAS

AVED

The first case of inherited isolated vitamin Eeficiency was reported in 1981 by Burck et al.1

or 10 years, this entity was considered extremelyare, until the discovery of an important foundingroup in North Africa.2-4 Age of onset is com-only around 10 years, but ranges from 2 to 52

ears in exceptional cases.In its classical form, AVED is very similar to FA

nd is defined by trunk and gait ataxia, positiveomberg’s sign, dysarthria, reduced position andibration sense, loss of deep tendon reflexes, andxtensor plantar response in the lower limbs. Itiffers from FA, however, by the absence of car-iomyopathy and diabetes and by the presence ofead titubation in 28% of cases and of dystonia innother 13% of cases.4 In the absence of supple-entation treatment, patients will eventually be-

From the Institut de Genetique et de Biologie Moleculaire etellulaire, CNRS/INSERM/Universite Louis-Pasteur, Illkirch,rance.Address reprint requests to Michel Koenig, Institut de Gene-

ique et de Biologie Moleculaire et Celullaire, CNRS/INSERM/niversite Louis-Pasteur, 1 rue Laurent Fries BP 163, 67404

llkirch, France.© 2003 Elsevier Inc. All rights reserved.1071-9091/03/1003-0000$30.00/0

2003 Elsevier Inc. All rights reserved.

doi:10.1016/S1071-9091(03)00027-5

183-192

come wheelchair bound after a mean 13 years ofdisease duration and may develop retinitis pigmen-tosa.5-7 The pathological study of a single caserevealed severe demyelination of the posterior col-umns of the spinal cord and severe atrophy of thesensory nuclei of the medulla, significant loss ofcerebellar Purkinje cells, and moderate atrophy ofthe lateral pyramidal tracts in the spinal cord and ofthe dorsal root ganglia and peripheral nerves.8

Electrophysiologically, the sensory action poten-tials are altered less and later than in FA.9 Anotherimportant histological feature is widespread neu-ronal and muscular lipofucsin accumulation. Thelipofucsin deposits are autofluorescent, electrondense, membrane bound, and phosphatase acidpositive, suggesting a lysosomal origin.1,10-13

These deposits are thought to represent lipoperoxi-dation products resulting from the absence of li-pophilic antioxidative properties of vitamin E. In-dicators of lipid peroxidation (eg, vulnerability oferythrocyte membranes, presence of thiobarbituricacid-reactive substances in blood) are positive.14-16

However, red blood cells morphology is normal,and no acanthocytes are present.1,10,11,17

Diagnosis of AVED is made by low serumvitamin E levels in the absence of fat malabsorp-tion. Serum vitamin E levels are well below thenormal range (�2,5 mg/L, often �1 mg/L [normalrange, 6 to 15 mg/L). Fat malabsorption should beexcluded by normal lipidogram results, with nor-mal levels of triglycerides, cholesterol, beta-li-poprotein, and other liposoluble vitamins (A, D,and K). Parents and carriers often have vitamin Evalues at the lower limit of the normal range.3,17

Normally, vitamin E is absorbed and secretedfrom the intestine into plasma in chylomicrons.During chylomicron catabolism in the plasma, vi-tamin E is transferred to circulating lipoproteinparticles (low-, intermediate-, and high-density li-poprotein), which can deliver vitamin E to tissues.The chylomicron remnants are taken up by theliver, which then selects only RRR-�-tocopherolstereoisomer from all of the forms of vitamin E forsecretion in nascent very-low-density lipoproteins(VLDL).18 Thus RRR-�-tocopherol represents thealmost exclusive form of circulating vitamin E inplasma. Other isomers and stereoisomers are elim-inated, presumably through the bile. The specifictransfer of vitamin E to nascent VLDL is the workof a liver-specific protein, �-tocopherol trans-

fer protein (�-TTP),19 which is defective inAVED.20,21 Patients with AVED absorb vitamin Enormally, but their conservation of plasma RRR-�-tocopherol is poor due to impaired secretion ofRRR-�-tocopherol in VLDL.22,23 In the absence ofrecycling, the entire plasma pool of vitamin E israpidly eliminated in a little more than a day.24

The human �-TTP gene, on chromosome 8q13,is composed of five exons and encodes a 278–amino acid protein that exhibits structural homol-ogies with the cellular retinaldehyde-binding pro-tein, which is present only in the retina, and theyeast Sec14 protein, involved in phosphatidylino-sitol and phosphatidylcholine transfer into mem-branes.25 AVED mutations are scattered through-out all five exons. In Tunisia, AVED is as commonas FA, due to the spread of the founder mutation744delA, which is also present in the other NorthAfrican countries, Italy, and France. All but oneNorth African AVED patient were found to behomozygous for the 744delA mutation, whereasthe 513insTT mutation is the major mutation seenacross Europe and North America.4 The most com-mon mutation found in Japan is a missense change,H101Q, associated with a very mild phenotype andlate onset.5,20

Patients with AVED exhibit no limitation ordifficulty with vitamin E absorption by the intesti-nal tract. The administration of vitamin E supple-ments in divided doses daily has stopped the pro-gression of neurologic signs and symptoms andeven some amelioration of established neurologicabnormalities in a number of patients.14,26 Inadults, administration of 800 mg of RRR-�-to-copherol given twice daily with meals containingfat results in plasma �-tocopherol levels within orabove the normal range.4 The significant numberof new cases recently reported indicates thatAVED is not as rare as once thought, stressingagain the importance of not missing the diagnosisin this treatable condition and of instituting therapypromptly.

ABL

The first report of ABL, from a consanguineousfamily with two affected children, was published in1950 by Bassen and Kornzweig.27 In 1958, Jampeland Falls28 identified a deficiency in cholesteroland triglycerides in ABL associated with a defi-ciency of plasma lipid transport, causing a defi-

184 MICHEL KOENIG

ciency of the lipophylic vitamins A, K, and espe-cially E. ABL presents initially in the neonatalperiod with gastrointestinal manifestations relatedto malabsorption of fat, including vomiting, diar-rhea, and failure to gain weight normally.29 Endos-copy reveals a yellow discoloration of the duode-num, and evaluation of intestinal mucosa biopsyspecimens reveals vacuolization of the cytoplasmof villus cells that are fat-engorged but otherwisemorphologically normal, unlike in celiac disease,with which ABL is frequently confused. The in-testinal symptoms tend to diminish with age, re-flecting in part a striking aversion of many patientsto dietary fat.

In the absence of vitamin E supplementation,progressive neurologic and visual manifestationsappear. The neurologic manifestations mimic thoseof FA, beginning with diminished deep tendonreflexes and followed by loss of vibration senseand proprioception and finally appearance of anataxic gait, dysarthria, pes cavus, pes equinovarus,and kyphoscoliosis. The characteristic sites of thedegenerative process are the large sensory neuronsof the dorsal root ganglia and their myelinatedaxons that enter the spinal cord lateral to theposterior funiculus. The axons degenerate, leadingto a secondary demyelination of the posterior col-umns. As in isolated vitamin E deficiency, evalu-ation of muscle biopsy specimens after a longdisease duration reveal accumulation of ceroid andlipofuscin pigments. The most prominent ophthal-mic abnormality is pigmentary retinal degenerationwith involvement of the posterior fundus and lossor attenuation of the pigmented epithelium. Thepresence of lipofuscin pigment in the retina sug-gests that vitamin E deficiency plays a central rolein the retinopathy, although the combined defi-ciency of n-3 type essential fatty acids is a likelycontributing factor. Loss of night vision is a com-mon presenting symptom and may be related tomoderate vitamin A deficiency. Since the earlydescription of ABL, the abundant presence of ab-normal star-shaped erythrocytes, termed acantho-cytes, has been noted in peripheral blood. Theerythrocytes assume the acanthocytic form becauseof an abnormal composition of their membrane,which reflects the abnormal composition of theplasma lipoproteins.29 Severe anemia is commonand is the consequence of the malabsorption syn-drome.

Patients with ABL are virtually free of serumlipoproteins of the beta group (chylomicrons, LDL,and VLDL—that is, all lipoproteins that containbeta-apolipoproteins), resulting in reduced choles-terol levels (�500mg/l), almost undetectable tri-glyceride levels (�100 mg/l), and reduced levelsof lipophilic vitamins (E, A, and K) in the plasma,which, when combined with acanthocytosis, estab-lish the diagnosis of ABL. This deficiency is due tothe inability of intestine and liver cells to secreteB-100 lipoproteins.30 This inability is due not tomutations in the Apo B gene, but rather to muta-tions in the gene encoding the large subunit ofmicrosomal triglyceride transfer protein (MTP).31

The MTP gene, located on chromosome 4q23, iscomposed of 18 exons and is physiologically ex-pressed in intestinal, liver, and cardiac cells. MTPcan transfer triglycerides and cholesteryl estersbetween lipidic vesicles and is thought to promotethe acquisition of nonpolar lipids during or justafter completion of Apo B translation at the lumi-nal aspect of the rough endoplasmic reticulum.32 Itis likely that Apo B interacts physically with MTPduring the initial lipidation step. In the absence ofnormal initiation of Apo B-100 lipidation, Apo B isdegraded by intraluminal protease(s) and transportof plasma lipids is supplemented by apolipopro-teins E and A-II. Hypobetalipoproteinemia is arelated condition caused by mutation in the Apo Bgene. Whereas heterozygous individuals have onlyhypocholesterolemia, homozygous patients maydevelop neurologic signs and symptoms due tovitamin E deficiency. Significant vitamin E defi-ciency is found in patients having at least one ofthe two mutations resulting in alteration of both theshort and long Apo B isoforms (Apo B-40 and ApoB-100), by N-terminal truncation.

Treatment involves reduction of dietary fat toprevent steatorrhea and supplementation with vita-min E to prevent progression of the neurologic andretinal degenerative disease.29 A proportion of theingested fat can be replaced by medium-chaintriglycerides, which can be absorbed without theformation of chylomicrons, supplemented with es-sential fatty acids. Due to the malabsorption andlipoprotein abnormalities that make transfer intothe central nervous system extremely difficult, vi-tamin E supplementation requires the administra-tion of large oral doses, up to 150 mg of natural�-tocopherol per kilogram of body weight per day

185RARE FORMS OF GENETIC ATAXIA

in three divided doses. Repeated evaluation of thevitamin E status is necessary to monitor the effec-tiveness of treatment. Supplementation with water-soluble preparation of vitamin A also appears rea-sonable, but should be carefully monitored due tovitamin A’s toxic effects at high doses.

The primary defect causing FA, AVED, andABL sheds light on a possible general pathologicalscheme that would explain the shared sites ofdegeneration and shared “dying-back” axonal neu-ropathy. In FA, the disease is thought to resultfrom abnormal Fe-S cluster assembly, leading toincreased production of free-radicals, whereas inthe vitamin E ataxias, the disease appears to resultfrom reduced neuronal membrane defenses againstlipid peroxidation and other oxidative stress dam-ages.

Refsum’s Disease (RD)

In 1946, Sir Sigvald Refsum described a newneurologic entity he called heredopathia atacticapolyneuritiformis,33 which was subsequentlyshown to be due to phytanic acid accumulation.34

RD is defined by retinitis pigmentosa, peripheralpolyneuropathy, cerebellar and sensory ataxia, andelevated cerebrospinal fluid proteins in the absenceof pleocytosis.35 It usually presents between age 10and 20 years with retinitis pigmentosa, causingnight blindness and restricted peripheral vision thatcan progress to complete blindness. Anosmia iscommon. Ataxia develops later, associated withneuropathy. Sensorineural deafness, myopathy,and ichthyosis occur in more severe cases. Bonyabnormalities may be present, and if they are, theyare present early on. The most common abnormal-ity is shortening of the terminal phalanges of thethumb. Asymmetrical shortening of the fourthmetatarsal and other long-bone abnormalities arealso seen. In untreated patients, cardiac arrhythmiaand hypertrophic cardiomyopathy may develop.

The clinical biochemical feature is an elevatedplasma phytanic acid level to more than three timesthe upper limit of normal (ie, �100 �mol/l). Leftuntreated, phytanic acid accumulates in tissues andmay constitute up to 5% to 30% of total plasmafree fatty acids. Phytanic acid is an isoprenoid fattyacid derived from phytol, which is the alcoholanchor moiety of a chlorophyll molecule. Onlybacteria that occur in the digestive tract of herbi-vores and fishes can break down chlorophyll to

phytanic acid. Hence in humans, phytanic acid isexclusively of nutritional origin, mostly from dairyproducts and from the fat and meat of ruminantanimals and fishes. A years-long diet with foodcontaining no phytanic acid will eventually nor-malize phytanic acid levels in patients with RD.Green vegetables and many other foods, includingpork and poultry, contain little phytanic acid. Syn-thetic phytanic acid–free diets also exist. Ataxia,neuropathy, ichthyosis, and cardiac arrhythmia arethe symptoms that respond best to decreased bloodphytanic acid levels, whereas other manifestationsmay be irreversible. Plasmapheresis or lipapheresismay be used initially to rapidly achieve efficacy forsevere cases. Curiously, phytol is also the mem-brane anchor moiety of vitamine E, and nuclearorphan receptors that bind phytanic acid exist.Whether this may explain some of the clinicalsimilarities between RD and vitamin E deficienciesremains only speculative.

Accumulation of phytanic acid is due to thedeficiency of the first step of its degradation, whichis an alpha-oxidation that takes place in the per-oxisomes. This step yields pristanic acid, which isthen degraded by beta-oxidation in the mitochon-dria. The first step in alpha-oxidation involves analpha-hydroxylation of phytanoyl-CoA. Cloning ofthe phytanoyl-CoA hydroxylase (PhyH) gene andidentification of mutations therein allowed thedemonstration of this enzyme’s role in RD.36,37

The most common mutation is an in-frame deletionof 111 base pairs in the mid-region of the gene(135-246del111). However, RD is genetically het-erogeneous. Hypomorphic mutations in the PEX7gene, the complete loss of function of which wouldotherwise cause rhizomelic chondrodysplasiapunctata type I, were found to cause typical RD.38

PEX7 protein is the peroxisomal transporter thatspecifically imports proteins, such as PhyH, whichcontain a type 2 peroxisomal targeting signal pep-tide. The hypomorphic PEX7 mutations (mostlymissense changes) cause a partial deficiency oftype 2–targeted peroxisomal proteins, of whichPhyH seems to be the most affected.

Infantile-Onset Spinocerebellar Ataxia(IOSCA)

This form of ataxia, reported in 1985 by Kallioand Jauhiainen39 and in 1994 by Koskinen et al,40

so far has been found only in patients from Finland

186 MICHEL KOENIG

(in 21 patients belonging to 15 nuclear families).The disease manifests close to age 1 year as acuteor subacute clumsiness, athetoid movements in thehands and face, hypotonia, and loss of deep tendonreflexes in the legs. Ophthalmoplegia and sensori-neural hearing deficit are found by school age;sensory neuropathy (decreased or absent sensoryaction potentials) and optic atrophy, by age 10 to15; and female hypogonadism and epilepsy, by age15 to 20. Most patients are nonambulatory by age20. Ten of the 21 patients experienced seizures;eight of these had one or more acute crises thatprogressed to a therapy-resistant status epilepticusand lasted for 2 to 4 weeks.41 The fact that threepatients never regained consciousness and died intheir third decade of life suggests that life spanmay not be normal in patients with IOSCA.

The main pathological features of the disease aresensory axonal neuropathy (with severe loss ofespecially the large myelinated fibers) and progres-sive atrophy of the spinal cord, brain stem, and,eventually, cerebellum.42 Athetosis and epilepsydenote additional involvement of the cerebrum.

The gene defect of IOSCA has been localized tochromosome 10q24.1.43 All patients seem to shareone founder mutation, because they all bear acommon haplotype around the disease gene lo-cus.43 The smallest region of haplotype sharing,defined by a few ancient haplotype recombina-tions, is 150 kb and contains a single known gene,the paired-box protein 2, PAX2.44 However, nomutation has been found in the PAX2 gene inpatients with IOSCA. A disease-causing role fornucleotide changes in noncoding sequences is dif-ficult to assess, particularly because there are noethnically unrelated patients with linkage at thesame locus, which could pinpoint an independentmutation. Thus, identification of the molecular de-fect in IOSCA may prove difficult.

Ataxia Plus Blindness andDeafness (SCABD)

In 1974, van Bogaert and Martin45 reported afamily with autosomal recessive spinocerebellarataxia plus optic and cochleovestibular degenera-tion leading to deafness and blindness. We havereported a similar family, for which we demon-strated linkage to a 17-cM region on chromosome6p21-23.46 In our family, an uncle and a niece,both born from consanguineous parents, started

with gait ataxia at age 3 years. The niece had nocranial nerve involvement at age 6 but exhibitedslow responses on electroretinograms at age 14 andhad impaired hearing and vision by age 17. Theuncle was wheelchair-bound and almost deaf byage 27. Fundus examination revealed bilateral op-tic atrophy. Common causes of recessive ataxia,including mitochondrial diseases, were excluded.The identification of additional families linked to6p21-23 is needed to delineate a precise clinicalpresentation and progression for this condition.

CEREBELLAR ATAXIA PLUSSENSORIMOTOR NEUROPATHY

Ataxia and Oculomotor Apraxia 1 (AOA1)

The first known cases of AOA1 were two Jap-anese patients reported in 1971 by Inoue et al.47

Identification of the defective gene revealed thatthe disease is more common in Japan due to theoccurrence of two ancient founder mutations butthat it exists worldwide, with a major Caucasianfounder mutation. In 1988, Aicardi et al49 collectedreports of 14 AOA1 patients, 6 of whom werealready described in the literature. In 2001, Barbotet al50 reported 22 Portuguese cases, of which 14turned out to be defective for the AOA1 gene.

AOA1 is defined by early-onset (between age 2and 5 years) cerebellar ataxia, ocular apraxia, andareflexia indicative of peripheral axonal neuropa-thy, which translates later as a clinical motor neu-ropathy (causing neurogenic distal muscular atro-phy). Ocular apraxia involves the limitation ofocular movements on command dissociated frommovements of pursuit. In the case of AOA1, ocularapraxia is better defined by saccadic failure or slow(viscous) eye movements and indicates a neuronallesion in the pons rather than in the motor cortex,as exists in pure ocular apraxia. The cerebellum isseverely atrophic, whereas the brain stem and spi-nal cord are usually preserved. Dystonia and/orathetosis may be occasionally found. Patients oftenhave borderline intelligence. They may have anormal life span, although with severe motor def-icits, leading to loss of ambulation by age 15 years.

Localization of the defective gene to chromo-some 9p13.3 in Portuguese families demonstratedthat AOA1 is the same disorder as early-onsetcerebellar ataxia with hypoalbuminemia (EOCA-HA),51 described a few years earlier in Japan.52 As

187RARE FORMS OF GENETIC ATAXIA

such, both entities are characterized by reducedserum albumin and elevated cholesterol levels aftera long disease duration (usually 15 years). Thesebiochemical abnormalities (of hepatic, not renal,origin) cannot be used for early diagnosis. TheFRDA2 locus identified in 9p23-p1153 is presum-ably identical to AOA1. Date et al54 and ourgroup55 independently identified the AOA1 gene,which encodes for a novel HIT/Zn-finger proteinknown as aprataxin. Proteins containing a histidinetriad (HIT) domain are known to have nucleotidepolyphosphate hydrolase activity. We have alsoshown that the major isoform of aprataxin (ie, thelong isoform) encodes an additional domain re-lated to the N-terminal domain of polynucleotide5�kinase, 3�phosphatase (PNKP) involved in baseexcision repair (BER) of DNA single-strand breaks(SSB). Both this similarity and the nuclear local-ization prediction of aprataxin suggest thataprataxin might also be involved in SSB repair(SSBR),55 a conclusion also supported by the iden-tification of a direct interaction between aprataxinand XRCC1, another component of the SSBRcomplex.56 AOA1 is the most frequent cause ofrecessive ataxia in Japan, where two founder mu-tations (689insT and P206L) account for the vastmajority of cases.54,55 The W279X mutation,found in five of six Portuguese families,55 is alsowidespread and is by far the most common muta-tion in the caucasian population (M.-C. Moreira,personal communication, August 29, 2002). Themissense mutation P206L is associated with asomehow later onset (around age 10 years54,55),and the V263G and K197Q mutations are associ-ated with significantly milder presentations (onsetat 25 and 15 years, respectively54,57). Several DNArepair disorders, such as A-T, xeroderma pigmen-tosum, and Cockayne syndrome, involve cerebel-lar ataxia, neoplasia, and/or immunodeficiency.AOA1 shares the early-onset cerebellar ataxia andocular apraxia of A-T, but not the extraneurologicfeatures of A-T, suggesting that pathology relatedto partial BER deficiency might be restricted topostmitotic neuronal tissues. A second disease thatsupports this view is spinocerebellar ataxia plusneuropathy 1 (SCAN1).

SCAN1

SCAN1 shares with AOA1 the cerebellar atro-phy and axonal sensorimotor neuropathy, but not

ocular apraxia. SCAN1 also shares with AOA1 theborderline low serum albumin and high cholesterollevels. The entity was reported in a single multi-generational, consanguineous family with nine af-fected members.58 Age at onset ranged from 13 to15 years in three patients. SCAN1 is linked tochromosome 14q31 and is shown to be due to theH493R mutation in the tyrosyl-DNA phosphodies-terase 1 (TDP1) gene.58 TDP1 is an enzyme thatrepairs stalled covalently bound topoisiomeraseI-DNA complexes, which lead to single-strandbreaks during DNA unwinding. H493 is one of thetwo histidines of TDP1 that act as a nucleophilattacking the tyrosyl-DNA phospodiester bond.DNA breaks liberated from the tyrosyl moiety byTDP1 are then repaired by the BER pathway,including intervention of PNKP (see earlier). It istherefore possible that AOA1 and SCAN1 pathol-ogy proceed from the same biochemical pathwayin which aprataxin plays an as-yet unidentifiedrole.56

Ataxia Plus Oculomotor Apraxia 2 (AOA2)

The first AOA2 family was reported in 1998 byWatanabe et al.59 The four Japanese patients hadcerebellar atrophy and sensory neuropathy, but nooculomotor apraxia. Brain stem and spinal cordfunction was preserved. The four patients hadmoderately elevated alpha-fetoprotein, immuno-globulin, and creatine kinase blood levels. Thedefective gene was localized to 9q34.46 At thesame time, a large Pakistani family with AOA wasalso reported to be linked to 9q34.60 These fivepatients had normal alpha-fetoprotein, immuno-globulins and creatine kinase levels, however.Since then we have identified eight more poten-tially linked families, based on homozygosity ofpatients born from (remotely) consanguineous par-ents (unpublished results). Five families had mod-erately elevated serum alpha-fetoprotein levels,and four had oculomotor apraxia. Immunoglobulinand creatine kinase levels were normal, and theirelevation was presumably fortuitous in the firstreported family. Age at onset for all linked familiesranged from 14 to 22 years, which is significantlylater than for AOA1. It is likely that most of theadolescent-onset A-T–like patients with elevatedalpha-fetoprotein levels61,62 have AOA2 ratherthan hypomorphic ATM mutations. However,identification of the defective gene is necessary to

188 MICHEL KOENIG

precisely delineate the clinical features of thisentity.

CEREBELLAR ATAXIAS

Autosomal Recessive Spastic Ataxia ofCharlevoix-Saguenay (ARSACS)

More than 300 persons with ARSACS areknown to live in the province of Quebec, Canada,most of them in the region of Charlevoix-Saguenay. Molecularly proven cases of ARSACSoutside of Canada have so far been reported only inTunisia, but presumably also exist elsewhere. AR-SACS was first described by Bouchard et al in1978.63 ARSACS causes early and marked degen-eration of both the pyramidal tracts of the spinalcord and of the superior cerebellar vermis withsubsequent progressive cerebellar hemisphere at-rophy.64 Onset occurs at gait initiation (around 1 to2 years). Pyramidal signs dominate the clinicalpresentation. Spasticity of the lower limbs is thefirst sign; plantar response is always abnormal,either equivocal or indifferent in youngsters andextensor thereafter. Deep tendon reflexes are in-creased, often with clonus at the ankles and patel-lae in the early adulthood. Cerebellar signs aresparse at the beginning, but increase slowly fromadolescence on. They include gait ataxia, dysar-thria, and nystagmus. The eye signs are mosttypical of the disease. These early nonprogressivesigns include saccadic alteration of smooth ocularpursuit and prominent myelinated fibers radiatingfrom the optic disc and embedding part of theretinal blood vessels on fundoscopy.63,64 There isno visual deficit, however. The abnormal retinalmyelinated fibers were not seen in the Tunisianpatients.65 In the mid-20s, motor axonal polyneu-ropathy appears, resulting in absent ankle jerks.ARSACS patients become wheelchair-bound at amean age of 41, with a range of 17 to 57 years.Verbal IQ is usually within normal limits, but thehandling of visuospatial material is poor and dete-riorates over time.66,67 Some patients survive intotheir 70s, but become bedridden by that time. ThusARSACS is a very early-onset disease with fasterprogression in teenagers and young adults withsubsequent slow progression.

The ARSACS gene was localized to 13q11 in199968 and identified in 2000.69 It is a remarkableintron-less 13-kb long gene encoding for a novel

3829 residue protein known as sacsin. Sacsin con-tains repeated heat-shock domains, suggesting arole in chaperone-mediated protein folding. Some96% of the Quebec patients were homozygous forthe 6594delT founder mutation, and the remainingcases (two families) were compound heterozygotesfor the founder mutation and a 5254C3T non-sense mutation. Four Tunisian and two TurkishARSACs families have been identified by linkageanalysis,65,70 and all four Tunisian families bore adifferent mutation71 that was also different fromthe Canadian mutations. The diversity of mutationscausing ARSACS, including truncating mutations,indicates that ARSACS results from a completeloss of function of sacsin, a result that was initiallyunexpected given the high geographic clustering ofthe cases.

Cerebellar Ataxia With HypogonadotrophicHypogonadism

Holmes first described the association of cere-bellar ataxia and hypogonadism, sometimes calledGordon Holmes syndrome, in 1907.72 The hypo-gonadism of most patients with Gordon Holmessyndrome is hypogonadotrophic, with a defect inthe production or release of gonadotropins by thepituitary gland. In the absence of treatment, hy-pogonadotropism is reflected in failure of second-ary sexual characteristics, eunuchoidism, absenceof libido, and infertility.73 Onset of ataxia mayfollow hypogonadism by 12 to 30 years. Magneticresonance imaging or computed tomography scansreveal cerebellar atrophy.74 Gordon Holmes syn-drome is sometimes associated with chorioretinaldystrophy, in which case it is called Boucher-Neuhauser syndrome.75,76 No genetic localizationhas yet been identified for Gordon Holmes orBoucher-Neuhauser syndromes.

CONCLUSIONS

The unravelling of the molecular cause of agrowing number of recessive ataxias has revealedthat these often rare diseases are the consequencesof a large variety of different mechanisms, eveninvolving novel, unsuspected molecular pathways.But the functions of the sometimes novel proteinsencoded by the defective genes identified to datesuggest that the recessive ataxias involving primar-ily the spinal cord or the cerebellum may proceedfrom two distinct general pathways. On one hand,

189RARE FORMS OF GENETIC ATAXIA

FA and the vitamin E deficiency ataxias, involvingprimarily the spinal cord, appear to result fromincreased production of or lack of protectionagainst free-radical damages, whereas A-T, AOA1,SCAN1, and MRE11 partial deficiency77 appear toresult from impaired DNA single- or double-strandbreak repair. Further studies on the newly identi-fied proteins defective in recessive ataxias andidentification of the predictably numerous newgenes involved in recessive ataxias when defectiveshould tell whether this trend is biased by the small

number of identified genes or whether it reflectsgeneral pathological neurodegenerative mecha-nisms that could be amenable to therapy.

ACKNOWLEDGEMENTS

The author thanks his close collaborators who were deeplyinvolved in some of the studies, in particular Nathalie Doer-flinger, Karim Ouahchi, Laurent Cavalier, Pascale Bomont,Maria-Ceu Moreira, Moez Gribaa, Clotilde Lagier-Tourenne,and Sandra Klur, as well as the numerous clinicians andfamilies for their active collaboration.

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