Neurogenetics (1998) 1 : 165–177
Q Springer-Verlag 1998
Review article
Clinical and molecular genetics of primary dystonias Ulrich Müller 7 Daniela Steinberger 7 Andrea H. Németh
Received: January 12, 1998 / Accepted: January 19, 1998
ABSTRACT
INTRODUCTION
Primary dystonias are movement disorders with dystonia as a major symptom. They are frequently inherited as Mendelian traits. There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms. In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant. The clinical classification is increasingly being replaced by a genetic one. To date gene loci have been identified in at least six autosomal dominant forms, i.e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21q22), dopa-responsive dystonia (14q22.1-q22.2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21p13.3). Gene loci in the X-linked recessive forms have been assigned to Xq13.1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation. The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form. Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in doparesponsive dystonia (DYT5). In sensorineural deafness, dystonia, and mental retardation, mutations were found in the gene DDP coding for a polypeptide of unknown function. This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1–12.
Dystonia is a disorder of movement characterized by “involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements, or abnormal postures” [1, 2]. Primary forms of dystonia can be distinguished from secondary ones. Primary dystonia occurs either in a familial or sporadic pattern with dystonia as the sole or major symptom. In contrast, “secondary dystonia” refers to dystonia in the context of a neurological disease in which dystonia is usually one of several symptoms or in which dystonia is the result of an environmental insult [2, 3]. The primary dystonias can be further subdivided by clinical criteria such as the age of onset, the distribution of affected body parts, presence of diurnal variation of symptoms, and responsiveness to drugs, as well as by genetic criteria. Our knowledge of the molecular genetics of primary dystonias has increased dramatically during this decade. When we reviewed the genetics of primary dystonias 8 years ago, the various forms were primarily classified by clinical criteria. Only two types [early-onset autosomal dominant dystonia and X-linked recessive dystonia-parkinsonism (XDP)] could be distinguished genetically. Now at least eight types can be differentiated by genetic analysis, and the gene defect has been identified beyond doubt in three types. These findings are a first step towards an understanding of the pathological mechanism of dystonias at the molecular level. Here we give an update on our current understanding of the clinical and molecular genetics of primary dystonias.
Key words Primary dystonia 7 Dystonia parkinsonism syndromes
CLASSIFICATION OF PRIMARY DYSTONIAS
U. Müller (Y) 7 D. Steinberger Institut für Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, D-35392 Giessen, Germany Tel: c49 641 99 41 600; Fax: c49 641 99 41 609 e-mail:
[email protected] A.H. Németh Wellcome Trust Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK
Until recently, classification of the primary dystonias was primarily based on clinical criteria, such as age of onset or the distribution of body parts affected by the dystonia. In many cases conclusive assignment of a given phenotype was not possible due to the pronounced phenotypic variability in dystonia. Advances in molecular genetics now allow the definitive distinction of many forms. At least six different gene loci have been identified in autosomal dominant dystonias and two loci have
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been established in X-linked recessive forms. Three autosomal dominant dystonias are presently delineated mainly clinically; and several additional types of primary dystonias have been distinguished by clinical and classical genetic criteria. Presently, however, it is not known whether the latter do indeed represent distinct nosological entities (Table 1).
DYSTONIA 1 [Autosomal dominant, early-onset dystonia; idiopathic torsion dystonia (ITD); Locus DYT1] Autosomal dominant, early-onset dystonia (idiopathic torsion dystonia, ITD, locus DYT1) has been recognized as a distinct nosological entity since the beginning of this century [4, 5]. The onset is usually in childhood. The first symptoms are focal and occur in the upper or lower extremities. Dystonia frequently generalizes within about 5 years. There appears to be a correlation between the site of onset and the course of the disease. Prognosis is worst and generalization of dystonia most likely if the first symptoms occur in the legs [6]. Although onset is usually in childhood, it can vary from between 4 and 80 years [7]. Adult-onset forms of dystonia rarely begin in the lower extremities, tend to be less severe than early-onset forms, and remain focal or
segmental in most cases [8]. Symptoms and signs observed in dystonia are given in Table 2. The disorder is most likely caused by a malfunction of the basal ganglia. Given that there are no neuropathological findings in ITD, and that striatal [18F] dopa uptake is reduced in severe cases [9], malfunction of the basal ganglia is probably due to a biochemical disturbance rather than a structural or degenerative abnormality. A genetic etiology was postulated for early-onset ITD as early as 1911 [10] and an autosomal dominant mode of inheritance is now well established. Penetrance is usually low (approximately 30%, [11, 12]) but varies considerably between families. In one particularly large family of 146 members, first described by Johnson et al. [13], torsion dystonia was expressed with a penetrance greater than 90% [14, 15]. Age of onset of affected family members ranged from 6 to 42 years and severity of the disease varied considerably, with earlyonset cases being most severely affected. Autosomal dominant dystonia has been observed in many populations with the highest prevalence (1 in 17,000–1 in 36,000) in Ashkenazi Jews. In this population the gene frequency was estimated at 1in 6,000 [16]. In non-Jewish populations the gene frequency is much lower (1 in 200,000, [17]). The high prevalence of dystonia in Ashkenazim is due to a founder mutation which probably appeared first in Lithuania or Byelorussia approximately 350 years ago [16].
Table 1 Classification of primary dystonia (AD autosomal dominant, XR X-linked recessive) Designation
OMIM
Mode of Locus inheritance
Dystonia 1; AD, early-onset dystonia; idiopathic torsion dystonia (ITD)
128 100
AD
DYT1
Dystonia 7; focal, adult-onset ITD, idiopathic focal dystonia
602 124
AD
DYT7
AD
DYT6
8p21–8p22
Dystonia 6; adult-onset ITD of mixed type
Chromosomal location 9q34 18p
Mutation in gene coding for ATP-binding protein P
Dystonia 5; dopa-responsive dystonia (DRD); hereditary progressive dystonia with marked diurnal fluctuation; Segawa syndrome
128 230
AD
DYT5
14q22.1–q22.2
191 290
AR
P
11p15.5
Dystonia 8, 9; paroxysmal dystonic choreoathetosis; familial dyskinesia; Mount-Reback syndrome
118 800
AD
PNKC CSE
Dystonia 10; paroxysmal dystonia; kinesigenic choreoathetosis
128 200
AD
P
P
P
Dystonia 11; myoclonic dystonia; alcohol-responsive dystonia
159 900
AD
P
P
P
Dystonia 12; rapid-onset dystonia parkinsonism
128 235
AD
P
P
P
Dystonia 4; torsion dystonia 4
128 101
AD
DYT4
P
P
Dystonia 2; autosomal recessive dystonia, DYT2 dystonia
224 500
AR
DYT2
P
P
Dystonia 3; X-linked dystonia parkinsonism syndrome (XDP)
314 250
XR
DYT3
Xq13.1
P
X-linked sensorineural deafness, dystonia, mental retardation; Mohr-Tranebjaerg syndrome; DFN-1/MTS
304 700
XR
DFN-1/MTS Xq22
2q33–q25 1p21–p13.3
GTP cyclohydrolase 1 Tyrosine hydroxylase P P
DDP
167 Table 2 Symptoms and signs of dystonia (adapted from [2]) Name
Affected musculature
Symptoms
Blepharospasm
Orbicularis oculi and neighboring facial muscles
Initially, these may be photophobia and ocular discomfort and excessive blinking. Forced closure of the eyelids caused by increasingly lengthy spasms rendering the patient functionally blind Involvement of jaw and neck muscles with blepharospasm is known as Meige’s syndrome
Oromandibular dystonia
Muscles innervated by cranial nerves V, VII, X, and XII
Spasms of jaw opening or closing, jaw deviation, tongue protrusion, lip smacking, sometimes minor twitching of oral region
Spasmodic dysphonia
Laryngeal muscles
When adductor muscles are affected (most common type) the voice is strained, harsh, and strangulated, may be tremulous and jerky When abductor muscles are affected voice is weak and breathy (often mistaken for a psychiatric condition) There may be mixed types
Dystonic dysphagia
Pharyngeal muscles
Difficulty with swallowing
Torticollis
Sternocleidomastoid, trapezius, splenius capitis, scalenes, semispinalis, and other nuchal muscles
Rotation, tilting, flexion, extension, lateral or sagittal shift of neck and head, elevation of shoulder May be tonic or associated with head tremor or irregular jerking movements
Writer’s cramp
Muscles of hand, forearm, and arm
One of “task-specific” or “occupational” dystonias: symptoms occur predominantly when one specific movement is initiated; symptoms can spread to include related movements Other examples are keyboard operators, musicians, and sport-related cramps
Leg dystonia
Muscles of foot, leg, and thigh (e.g., gastrocnemius, tibialis posterior, flexor digitorum brevis)
Spasmodic flexion or inversion of feet, bizarre gait with flexion of knees and thighs
Scoliosis, lordosis, kyphosis, tortipelvis
Muscles of back
Twisting, writhing, and arching movements of trunk and pelvis
The large family of Johnson et al. [13] was reexamined by Ozelius et al. [18]. By this time there were 165 members, of whom 73 were available for neurological examination and DNA analysis. There were 14 clearly affected individuals and the penetrance was estimated at 75%, somewhat lower than originally assumed. Linkage analysis with polymorphic DNA markers assigned the disease locus, DYT1, to the distal long arm of chromosome 9 (9q32-q34). In Ashkenazim the disease locus was also assigned to this interval, suggesting that the same gene is mutated in both Jewish and non-Jewish individuals with ITD [19]. Linkage analyses in additional Jewish and non-Jewish families further narrowed down the disease locus to 9q34 [20]. Previously, strong allelic association (linkage disequilibrium) had been observed between polymorphic markers in 9q34 and DYT1 in patients of Ashkenazi Jewish decent [21]. This placed DYT1 in a region of 1–2 cM centromeric to locus ASS (Fig. 1, [21]). A YAC contig was then constructed across a 600-kilobase pair (kb) interval containing DYT1. Analysis of recombination events and allelic association studies narrowed the critical interval down to approximately 150 kb [22] (Fig. 1). The critical region was subsequently cloned in cosmids, four transcripts were identified by exon trapping in this contig, and cDNAs (DQ1–DQ4) were isolated. Mutation anal-
ysis of the four cDNAs revealed numerous neutral nucleotide changes (polymorphisms) and an in-frame trinucleotide deletion (GAG) in DQ2 that was confined to patients. Studying a large number of patients from different ethnic backgrounds, the GAG deletion was the only mutation detected [23]. Most (90%) patients with an atypical presentation did not have any identifiable mutation in DQ2. Interestingly, at least four different background haplotypes were seen, but only one mutation was found, suggesting that the same GAG deletion has arisen more than once to cause ITD. DQ2 has an open reading frame of 998 base pairs (bp), which is predicted to code for a polypeptide of 332 amino acids. The gene is alternatively spliced. Northern analysis revealed two ubiquitously expressed transcripts of 1.8 kb and 2.2 kb and an additional low-abundance transcript of 5 kb that was detected in fetal brain, lung, and kidney, and in adult brain, heart, and pancreas. The gene product has homology with an ATP-binding protein and is evolutionarily highly conserved. Its role in the pathology of dystonia is presently not understood. Given the highly variable phenotype observed in ITD, the identification of DYT1 is a major advance for the accurate diagnosis of this condition.
168 Fig. 1 Location of DYT1 on chromosome 9, adapted from Ozelius et al. [22]
DYSTONIA 7 [Focal, adult-onset idiopathic torsion dystonia; idiopathic focal dystonia (IFD); Locus: DYT7] Dystonias that remain focal usually have an adult onset but with an age range from adolescence to late life. Patients present with symptoms affecting one body part, most frequently the neck (spasmodic torticollis), eyes (blepharospasm), and hands (writer’s cramp). Patients with purely focal dystonias rarely present with symptoms in the lower limbs. Although symptoms may spread to adjacent segments of the body, dystonia rarely generalizes. As in early-onset ITD, no neuropathological changes have been identified. Several studies have suggested that focal dystonias have a genetic basis. The proportion of inherited versus sporadic cases, however, is not yet known. Based on surveys and home visits, Waddy et al. [24] suggested that approximately 25% of patients have a positive family history. Studies of the prevalence of focal dystonia suggest that it occurs in 1–3 in 10,000 of the European [25] and 6 in 100,000 in the Japanese population [26]. Since these estimates are from adult-based neurology clinics rather than population based, they are likely to underestimate the actual prevalence. Leube et al. [27] studied a large family with focal autosomal dominant ITD (family K). Seven family members had definite dystonia (6 torticollis, and 1 spasmodic dysphonia) and 6 had possible dystonia. Of the latter, 5 had signs of torticollis such as muscular hypertrophy and minimal rotation of the head, and 1 presented with postural tremor of the hands. Postural hand tremor was also observed in 3 definitely and 3 possibly affected individuals. Mean age of disease onset in this family was 43 years (range 28–70 years). Linkage analysis in this family indicates a disease locus on the short arm of chromosome 18. The highest LOD score was found with marker D18S452 (Zmax p 2.68 at u p 0.0). Analysis of a haplotype consisting of five individual loci (D18S967, D18S62, D18S471, D18S458, D18S452) as a single locus resulted
in a LOD score of 3.17 at u p 0. Haplotype analysis in this family suggested the location of the disease gene telomeric to locus D18S1153. Leube et al. [28, 29] performed haplotype analyses with markers from 18p in not obviously related patients with adult-onset idiopathic focal dystonia from the same region as family K (northwestern Germany) and from central Europe (primarily Germany and Poland). The authors found that some but not all patients had comparable haplotypes. This might indicate that individuals with the same haplotypes carry the same mutation as affected members of the large family K. According to this interpretation, the mutation on 18p has arisen in a common ancestor (“founder effect”) and spread throughout central Europe as an autosomal dominant trait with low penetrance [28, 29]. Proof of this hypothesis will require identification of the DYT7 gene.
DYSTONIA 6 [Adult-onset idiopathic torsion dystonia of mixed type; Locus: DYT6] Almasy et al. [30] performed clinical and genetic analyses of ITD in two not obviously related Mennonite families. Of 220 family members, a total of 15 definitely affected individuals were identified. Some affected individuals had a phenotype indistinguishable from that seen in patients with the DYT1 mutation. However, the age of onset in these patients was later (average 18.9 years vs. 13.6) and the distribution of affected body parts different from those with the DYT1 mutation. In patients with the DYT1 mutation symptoms start in a limb and spread to other limbs and the axial musculature, with laryngeal muscles rarely affected. In contrast, about half of the patients from the Mennonite families presented with cranial or cervical involvement, and those who presented with limb symptoms later developed cranial or cervical symptoms. In 2 cases the symptoms remained localized. The type of dystonia observed in these 2 families can be referred to as adult-onset ITD
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of mixed type (DYT6). Linkage analysis in these families has mapped the disease gene to chromosome 8 (8p21-8q22) with a maximum LOD score of 3.69 at u p 0.00 for marker D8S1797 in family “M” and 2.11 in family “C”, giving a combined maximum LOD score of 5.80 at D8S1797. Inferred haplotypes across the candidate region were identical in affected members of both families, suggesting a founder effect and common mutation.
DYSTONIA 5 [Dopa-responsive dystonia (DRD); hereditary progressive dystonia with marked diurnal fluctuation (HPD); Segawa syndrome; Locus: DYT5] Dopa-responsive dystonia (DRD) is characterized by dystonia, concurrent or subsequent parkinsonism, a dramatic therapeutic response to L-dopa in most patients and diurnal worsening of symptoms in about 75% of index cases [31]. Symptoms and age of onset vary considerably between patients. Although onset is usually during childhood or adolescence, adult onset does occur. Furthermore, some patients have focal dystonias or minor symptoms, such as abnormal positioning of one foot, while others have generalized dystonia and are wheelchair bound if untreated [32]. In childhood, DRD may present with a phenotype resembling atypical cerebral palsy [33, 34], while in adulthood DRD can present with parkinsonian tremor and rigidity as well as brisk tendon reflexes and extensor plantars [35]. Due to this wide spectrum of symptoms and age of onset (summarized in Table 3), the disorder is frequently not recognized and misdiagnoses can occur. Thus the commonly observed pes equinovarus can be mistaken as an orthopedic problem and treated by achillectomy. The circadian variation and nature of symptoms can be misinterpreted as a psychiatric condition, and adult-onset parkinsonism in some DRD patients can be confused with the common forms of Parkinson disease [36]. The prevalence of DRD is assumed to be 0.5–1.0 ! 10 –6 [37], but may in fact be considerably higher. Women are affected 2–4 times more frequently than men [32, 37, 38]. DRD is inherited as an autosomal dominant trait with reduced penetrance. Based primarily on findings in one large family, a penetrance of about 30% is generally assumed [39]. Taking into account subtle signs and symptoms, however, penetrance is higher and can range from 40% to 100%. Male gene carriers are more likely to be asymptomatic than females [36]. Linkage analyses in DRD families have assigned the disease locus, DYT5, to chromosome 14 (14q11-q24.3) [37]. Subsequently, analysis of candidate genes in patients revealed mutations in GCH1 located in 14q22.1q22.2 as the cause for DRD in three of four families examined and in one sporadic case [38]. GCH1 codes for GTP cyclohydrolase I (GTPCH I) which is the rate-limiting enzyme in the biosynthesis of
Table 3 Symtpoms and signs in DRD Objective findings Blepharospasm Oromandibular dystonia Torticollis External rotation of arms Dystonia of individual fingers Writer’s cramp Tremor (hands) Abnormal posturing of shoulders Truncal dystonia Scoliosis/hyperlordosis Shortening of legs Supination of feet or pes equinus Spontaneous dorsal or plantar extension of digits of feet Fixed hyerpflexion of digits (feet) Abnormal gait or inability to walk Spontaneous inability to finish a movement Parkinsonism Diurnal fluctuation Subjective complaints Pretibial pain Trembling of thighs Muscle tension and spasms Rapid fatiguability
tetrahydrobiopterin (BH4). BH4 in turn is an essential cofactor for the three amino acid monooxygenases phenylalanine-, tyrosine-, and tryptophan hydroxylase. Phenylalanine hydroxylase catalyzes the conversion of phenylalanine to tyrosine, tyrosine hydroxylase is required for the synthesis of L-dopa and dopamine and for the subsequent production of adrenaline and noradrenaline, and tryptophan hydroxylase is essential for the synthesis of serotonin (Fig. 2). Reduced activity of GTPCH I in DRD patients is thought to cause symptoms by depletion of dopamine. This assumption is consistent with the observed pronounced therapeutic effect of L-dopa, even in patients who have been severely incapacitated for years. GCH1 is composed of six exons (Fig. 3). Mutations have been found in all exons in DRD patients and are listed in Table 4. Interestingly, the majority of mutations result in truncation of the enzyme, either due to the introduction of a stop codon, a frameshift mutation, or abnormal splicing. Patients who are heterozygous for GCH1 mutations develop the clinical syndrome of DRD, whereas individuals who are homozygotes or compound heterozygotes for GCH1 mutations develop hyperphenylalaninemia with accompanying deficiency of dopamine and serotonin (“atypical phenylketonuria” [40]). This suggests that autosomal dominant DRD is caused by haploinsufficiency of GTPCH1. However, patients with DRD have enzyme levels which are approximately 20% of normal, rather than the expected 50%, suggesting that mechanisms other than the inactivation of one copy of the enzyme are also involved in the regulation of GTPCH1 levels. In fact, Hirano et al. [41] observed a point mutation in exon 5 of one allele of GCH1. Studying transcripts of this patient, they ob-
170
generating non-functional heteromultimers. The more frequent occurrence of DRD in females than males may be explained by higher base levels of GTPCH I activity in males than in females [38]. Due to this sex difference, one intact copy of the gene is more likely in males than in females to generate sufficient quantities of the enzyme to render the mutation carrier asymptomatic. Autosomal recessive inheritance may also occur in DRD. Mutations in the tyrosine hydroxylase gene in 11p15.5 have been reported in two siblings with Segawa syndrome [42]. A C]A transversion was described in exon 11 (codon 381) of the tyrosine hydroxylase gene in these two individuals. However, the results reported are not entirely convincing. The investigators did not provide linkage data to indicate that the disorder indeed maps to chromosome 11p15.5 in the family studied. Furthermore, sequencing was confined to one strand only. Finally, sequencing results obtained in the parents were not shown. In vitro studies by the same group indicate that the mutation described (now given as a C]T transition!) in the two siblings results in reduced activity of tyrosine hydroxylase [43].
Fig. 2 Pteridine pathway. Role of GTP cyclohydrolase 1 (GTPCH1) in the synthesis of L-dopa (GTP Guanosine triphosphate, NH2TP dihydroneopterin triphosphate, 6-PTH4P 6-pyruvoyltetrahydropterin, BH4 tetrahydrobiopterin, qBH2 quinoid dihydrobiopterin, 6-PTS 6-pyruvoyltetrahydropterin synthase, SR sepiapterin reductase, PAH phenylalanine hydroxylase, TH tyrosine hydroxylase, TRPH tryptophan hydroxylase, Phe phenylalanine, Tyr tyrosine, Trp tryptophan, DHPR dihydropteridine reductase, iG indicates use of BH4 as a cofactor)
served an alternatively spliced variant that lacks exon 5 and parts of exon 6, in addition to the predominant transcripts of the wild type allele. The authors speculate that the abnormal polypeptide coded for by the mutant RNA interacts with wild type polypeptides thus
Fig. 3 Location and genomic structure of the GTPCH I gene
DYSTONIA 8, 9 [Paroxysmal dystonic choreoathetosis (PDC); familial paroxysmal dyskinesia (FDP); Mount-Reback syndrome; Loci: PNKC and CSE] Paroxysmal dystonic choreoathetosis (PDC) was first described by Mount and Reback [44]. These authors described a large family with many members affected by paroxysmal choreoathetosis. PDC is characterized by attacks of dystonia, chorea, and athetosis occurring at rest [45, 46]. Age of disease onset varies widely and can be in early childhood, adolescence, or adulthood. The involuntary movements can be precipitated by alcohol, caffeine, and to a lesser extent by hunger, nicotine, fatigue, and emotional stress [47]. Unlike paroxysmal kinesigenic choreoathetosis, the episodes are not precipitated by sudden movements, exertion, or sleep. Episodes can last from minutes to hours and may occur several times a day. The disease can be quite disabling due to interference of the involuntary movements with walking, coordinated use of the arms and hands, speaking, chewing, and swallowing. Neurological examination between episodes is normal. PDC is inherited as an autosomal dominant trait with incomplete penetrance [48], and linkage analyses have been performed in two large families. The disease locus was assigned to the long arm of chromosome 2 in both families [48, 49]. However, the exact location reported for the two families was not entirely identical. One study mapped the PDC locus (PNKC) to 2q33-q35 [48] and the other study gives a more distal region in 2q (2q36) as the most likely critical interval of the disease gene (Fig. 2 of [49]). The slight discrepancies in locus assignment between the groups are most likely due to
171 Table 4 Mutations in GCH1 in DRD (n.d. not determined)
Exon
Nucleotide
Effect
Reference
1 1
ATG GAG]ATG GG GAG CCC]CTC
Frameshift Pro23Leu
1 1 1
GAG]TAG GAG]TAG TAC]TAA
Glu61TER Glu65TER Tyr75TER
1 1 1 1 1
CTG]CCG CGG]CCG CGG]TGG TCA]TAA CAG TTC]CA TTC Intron 1 a(P2) Intron 1 g(P1)a GAC]GTC CAC]CCC Intron 2 a (P2)g Intron 2 g(c1)c CAT]CCT 511 del 13bp GATTGTAGAAATCTAT AGA]AGC Intron 4 a(P2)c
Leu79Pro Arg88Pro Arg88Trp Ser114TER Frameshift Splicing mutation Splicing mutation Asp134Val His144Pro Splicing mutation Splicing mutation His153Pro Frameshift
[38] Fischer, Steinberger, Müller, unpublished data [90] [91] Fischer, Steinberger, Müller, unpublished data [92] [34] [38] [91] [36] [93] [91] [38] [94] [93] [95] [34] [92]
Intron 4 g(c1)c
n.d.
5
ACA]AAA
5 5 5
CAG]TAG GGA]GAA GGG]AGG Intron 5 ins (c3)T
Thr186Lys (plus additional transcript lacking exon 5 and part of exon 6) Gln182Stop Gly201Glu Gly203Arg n.d.
6 6 6
CGA]TGA AAA]AGA TTC]TCC
Arg216TER Lys224Arg Phe234Ser
2 2 3 4 4
analysis of different STRP (short tandem repeat polymorphism) loci that had been assigned to somewhat differing locations. The critical region of PNKC established by the two groups is given in Fig. 4. A cluster of sodium channel genes has been mapped on distal 2q and the authors discuss the possibility of mutations in one of these genes as the underlying cause of PDC. A second clinical syndrome of paroxysmal dyskinesia was studied by Auburger et al. [50]. Paroxysmal choreoathetosis, spasticity, and episodic ataxia is an autosomal dominant condition in which the involuntary movements and dystonia are similar to those in PDC. Age of onset was 2–15 years. Episodes of involuntary movements, dystonic posture of toes, legs, arms, dysarthria, paresthesias, and double vision lasted aproximately 20 min and occurred between twice a day to twice a year. Episodes could be induced by alcohol, fatigue, and emotional stress. However, unlike PDC, physical exercise could precipitate the episodes, and 5 of the 18 patients had spastic paraplegia both during and
Arg178Ser n.d.
[96] Fischer, Steinberger, Müller, unpublished data Fischer, Steinberger, Müller, unpublished data [41]
[36] [38] [34] Fischer, Steinberger, Müller, unpublished data [34] [34] [34]
between episodes of dyskinesia. The disease gene in this family was mapped to a 12-cM interval on 1p (1p21-p13.3). These studies suggest that PDC is clinically and genetically heterogeneous. Their clinical features distinguish them from other forms of dystonia and their paroxysmal qualities suggest that they may be “channelopathies,” such as those found in episodic ataxias and some myotonias [51–54].
DYSTONIA 10 [Paroxysmal familial dystonia; kinesigenic choreoathetosis (PKC)] This form of dystonia can be clearly distinguished clinically from PDC [55, 56]. Attacks are precipitated by sudden unexpected movements (“kinesigenic”), are of shorter duration (seconds to minutes), are more frequent, occurring up to 100 times per day, and usually
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families with “essential myoclonus” (dominantly inherited myoclonic dystonia with dramatic response to alcohol). The gene has not been located but has been excluded from 9q34, the location of DYT1, in a large Swedish family [59] and a large German family [60].
DYSTONIA 12 [Rapid-onset dystonia parkinsonism (RDP)]
Fig. 4 Chromosomal fine mapping of PNKC according to [48] and [49]: a corresponds to 2q33-q35 [48] and b corresponds to 2q36, according to Fig. 2 of [49] (PDC paroxysmal dystonic choreoathetosis) AE3 (SLC2C) is a candidate gene of PDC and encodes a sodium-independent anion exchanger
In rapid-onset dystonia parkinsonism, dystonia and parkinsonism develop within hours to weeks after disease onset, but less rapid courses with more gradual progression over 6–18 months have been described. Onset can occur during either childhood, adolescence, or adulthood [61–63]. In contrast to DRD, treatment with L-dopa is not very effective in this syndrome. Inheritance is autosomal dominant. A disease locus has not yet been assigned, but DYT1 has been excluded [61].
DYSTONIA 4 respond to anticonvulsant therapy. First symptoms tend to occur later in life than in PDC. Although most cases appear to be sporadic, both autosomal dominant and recessive modes of inheritance have been described. To date, no disease locus has been chromosomally mapped.
DYSTONIA 11
In various autosomal dominant forms of dystonia DYT1 was excluded as the disease locus [64–67]. The tentative locus designation DYT4 was assigned to these disorders. Given that an increasing number of disease genes are being identified in primary dystonias, we do not consider DYT4 a useful designation for this “mixed bag” of autosomal dominant disorders. Their correct designation will need to await linkage analysis.
[Myoclonic dystonia; alcohol-responsive dystonia] Dystonia can occur in combination with myoclonus (brisk, shock-like jerks of the limbs) and can be sporadic or hereditary. Quinn [57] has recently reviewed the nosology of this group of conditions. In “essential myoclonus” (“dominantly inherited myoclonic dystonia with dramatic response to alcohol”), symptoms develop in the 1st or 2nd decade, males and females are equally affected, and the condition is mild with most patients leading relatively normal lives. It is thought that “essential myoclonus” is quite rare and inheritance is autosomal dominant with variable penetrance. There are no seizures, dementia, or ataxia, the electroencephalogram is normal, and the response to alcohol is dramatic and may be diagnostic. Some patients have dystonia affecting the hands or neck, or occasionally the trunk or legs [58]. In contrast to “essential myoclonus” in which myoclonus is the constant feature and dystonia a “variable extra,” some patients with ITD have a tremor and rapid jerky movements which look like myoclonus [57]. The age of onset is variable, as is the pattern of body involvement, and myoclonus is an inconstant feature. Fewer patients have a positive family history than in “essential myoclonus” and the response to alcohol is variable. Linkage analysis has only been performed in
DYSTONIA 2 [Autosomal recessive dystonia; DYT2 dystonia] The existence of autosomal recessive forms of dystonias is controversial. Many cases of ITD which were originally thought to follow an autosomal recessive mode of inheritance have now been shown to be inherited as autosomal dominant traits with reduced penetrance. There are only a few pedigrees, mainly of consanguineous gypsies, still suggestive of autosomal recessive transmission of dystonia [68]. To date, however, no successful homozygosity mapping has been reported in these families and the occurrence of autosomal recessive inheritance remains uncertain. Therefore, the designation of DYT2 for this condition is currently not useful.
DYSTONIA 3 [X-linked dystonia parkinsonism syndrome (XDP); Locus: DYT3] The X-linked dystonia-parkinsonism syndrome (XDP) is a severe adult-onset movement disorder characterized by dystonia and frequently by concurrent parkin-
173
sonism [69, 70]. The mean age of onset is 35 B 8 years with a wide range (12–48 years). The disorder is initially focal and generalizes after a median duration of 5 years (range 1–11 years) [71, 72]. The first symptoms may either occur in the lower extemities (36%), the axial musculature (29%), the upper extremities (23%), or the head (12%). The site of onset does not affect the course of the disease, which is severely disabling in the majority of cases. Figure 5 shows three brothers, two of whom are affected by XDP. Parkinsonian symptoms, including bradykinesia, tremor, rigidity, and loss of postural reflexes, were described in approximately onethird of a total of 42 cases studied [71]. More recent neurological examinations of additional patients suggest that concurrent parkinsonism is even higher in XDP, with one or more parkinsonian symptoms being present in at least 50% of cases (Kupke and Müller, unpublished observation). There is no correlation between occurrence of parkinsonism and site of onset, the tempo of progression, or the general severity of the disorder. The older the age of onset, however, the likelier concurrent parkinsonism seems to be. Symptoms frequently observed in XDP are given in Table 5. Duration of illness can exceed 40 years, but shorter courses of the disorder are more common. Death usually occurs due to dysphagia and aspiration pneumonia. Examination of patients by computed tomography and magnetic resonance imaging does not demonstrate gross abnormalities in XDP. Positron emission tomographic analysis in three XDP patients revealed “selective reduction in normalized striatal glucose metablolism” [73]. Neuropathological investigations of the brain of a XDP patient revealed neuronal loss and astrocytosis in the caudate nucleus and the lateral putamen [74].
Inheritance of XDP is X-linked recessive [75, 76] and penetrance appears to be complete in male gene carriers by the end of the 5th decade. Although primarily males are affected, there are reports of three females with XDP who apparently carried two copies of the defective gene [77, 78]. Prevalence of XDP is highest in the Philippine island of Panay, where it originated from a single mutation (founder effect). Conservative estimates suggest 1 in 4,000 males to be affected in the Capiz province, Panay. XDP has also been reported in Filipino immigrants to the United States and Canada. Presently, the disorder has been diagnosed beyond doubt in people of Filipino extraction only. However, there are two reports of Caucasians with symptoms suggestive of XDP [79, 80]. Genetic analyses will eventually clarify the relationship between the disorder in Filipinos and non-Filipinos. The disease locus, DYT3, was assigned to the proximal long arm of the X chromosome [75] by two-point linkage analysis. Investigation of additional families and application of multi-point linkage analysis established flanking markers of DYT3 in Xq12-q21.1 [81]. Analysis of allelic association in 47 not apparently related XDP patients and in 105 unaffected Filipino male controls assigned DYT3 to Xq13 [82] and delineated the disease locus within 3 Mbp of Xq13.1 [83]. The critical interval has been further narrowed down within Xq13.1. A YAC contig was constructed of the region, novel short tandem repeat polymorphic markers (STRPs) were assigned to this contig, and tested for allelic association in patients and in controls. These studies assigned DYT3 to a small region in Xq13.1 defined by STRP loci DXS7117 and DXS559 ([84], Fig. 6). Several candidate genes have been identified in the critical interval of which two, p54 nrb and AFX1, have been excluded as being mutated in XDP [85]. Presently, indirect molecular diagnosis of XDP is possible in Filipino patients. More detailed molecular analyses, especially in non-Filipino patients with symptoms suggestive of XDP, will rely on the isolation of DYT3.
MOHR-TRANEBJAERG SYNDROME [X-linked sensorineural deafness, dystonia, mental retardation, cortical blindness; Locus: DFN-1/MTS] The simultaneous occurrence of deafness and dystonia was first described by Scribanu and Kennedy [86] in a Table 5 Commonly observed symptoms in XDP
Fig. 5 Three brothers from a family with X-linked dystonia-parkinsonism syndrome. The individual on the left is unaffected, the patients on the right have generalized dystonia. Note typical “mask face” of patient on the right
Common symptoms
Frequency (%)
Gait abnormalities Leg dystonia Oromandibular dystonia Neck dystonia Blepharospasm Truncal dystonia Parkinsonism
90 79 64 57 57 52 F50
174 Fig. 6 Fine mapping of DYT3 in Xq13.1 (data from [84]) (kb kilobases)
boy (proband) and his maternal uncle. In addition, deafness was observed in the proband’s nephew. In both proband and his uncle, deafness preceded dystonia. Dystonia started at age 7 years and progressed rapidly. The patient was wheelchair bound at 9 years and died at 11 years. Autopsy of the patient’s brain revealed “neuronal loss and gliosis in both caudate nuclei, putamen and globus pallidus.” More recently, Xlinked deafness associated with progressive dystonia, spasticity, dysphagia, mental retardation, and cortical blindness was observed in several pedigrees. In some patients, deafness and dystonia were the only symptoms. Other affected males displayed the main symptoms, including mental retardation, but were not blind. The syndrome is referred to as Mohr-Tranebjaerg syndrome (DFN-1/MTS) and appears to be a neurodegenerative disorder affecting the corticospinal tract, brain stem, and the basal ganglia [87–89]. Currently, it is not known whether the original patients described by Sribanu and Kennedy [86] had DFN1/MTS. The DFN-1/MTS locus was assigned to Xq21.3-q22 by linkage analysis [88]. Positional cloning identified the disease gene, DDP, in Xq22 [89]. DDP is composed of two exons separated by an intron of 2 kb. A 1.2-kb DDP transcript is detected in various tissues, including fetal and adult brain. In addition, alternative splicing products of 600 bp and 400 bp are detected in lower quantities in adult skeletal muscle, heart, and brain. DDP codes for a protein of 97 amino acids and has a molecular weight of 11 kilodaltons. The function of the DDP polypeptide is currently not known. Conclusion The clinical classification of primary dystonias is increasingly being replaced by a genetic one. Assessment of patients with dystonia now frequently requires molecular genetic analysis in addition to a family history and careful clinical examination. The use of molecular
genetic analysis also facilitates predictive and prenatal diagnosis. However, these advances in diagnostics require the availability of intensive professional guidance, particularly for those patients seeking predictive and prenatal testing. It is hoped that the advances in understanding the molecular genetics of dystonia will be useful in designing novel therapeutic regimes for this group of disabling conditions. Acknowledgements We would like to thank the Deutsche Forschungsgemeinschaft (grant Mu668/6–2) and the Medical Research Council (MRC) of Great Britain for financial support. A.H.N. is an MRC Clinician/Scientist fellow.
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