and ferritin in the brain due to a mutation in the ferritin light chain gene ( FTL1 ) (45). Fewer than 100 cases have been described. Patients present with chorea or dystonia with asymmetric limb involvement and sometimes evi dence of parkinsonism and ataxia (46). With time, orofacial dystonia develops, aff ecting s peech, and dysphagia can be a signifi cant problem. Eye movements are pre- served. A progre ssive frontal and subcortical cognitive decline has been described. Neurodegeneration with brain iron accumulation type 1 (NBIA-1) Th is term encompasses a num ber of disorders of iron accumulation in the brain, including those previously labeled Hall ervoden \200\223Spatz disease. Th e most common form is pantothenate kinase-associated neur odegeneration (PKAN) which accounts for approximately 50% of cases. Other disorders of iron accumulation include neuroferriti- nopathy and infantile neuroaxonal dystrophy. Serum ferritin is low, typically \211 20 g/dl (46), in the presence of normal serum ir on, transferrin, and hemoglobin levels. MRI in all patients demonstrates excess brain iron accumulation on T2* MRI in the putamen and globus pallidus, oft en with cystic changes. Mol ecular genetic testing for FTL is available. Neuropathology reveals iron and ferritin deposition both within neurons and extracellularly in the basal ganglia, forebrain, and cerebellum with accompanying neuronal loss. In mice e xpressing a mutant human form of the FTL gene, there was increased cyto- plasmic FTL, ferri tin heavy chain polypeptides, and iron (47). It was suggested that the pathogenesis in neur oferritinopathy resulted from a combination of reduction in iron-storage function and enhan ced toxicity associated with iron-induced ferritin aggregates in the brain. PKAN is a rare autosomal recessive disorder of co-enzyme A (CoA) metabolism. Estimated prev alence is 1 \200\2233 per million, sug- gesting a carrier frequency of 1 in 275 \200\223300 . Th e majority have mutations in the pantothenate kinase 2 gene. Onset is usually in the fi rst decade, but adult-onset cases have been described (40). Th e course of the disease is progressive over 10 \200\22312 years, although survival can be lo nger. PKAN can be famil- ial or sporadic. It is characterized clinically by prominent dysto nia (in up to 87%), parkinsonism, cognitive impairment, pseudobulbar features, spasticity, and cerebellar ataxia (40, 41). Limb dystonia can lead to children being considered to be c lumsy before other symp- toms emerge (41). Cranial dystonia can lead to recurrent trauma of the tongue, even leading to dental extraction. Axial dystonia occurs later in the course o f illness. Pigmentary retinopathy occurs in around two-thirds of cases, with night blindnes s and progressive peripheral visual fi eld loss. Intellectual involvement is variable, as a re seizures. Treatment is symptomatic and supportive, and no drugs have been shown to alter the course o f neuroferritinopathy. Th e role of iron chelation and venesection is under review. Infantile and atypical neuroaxonal dystrophy (INAD) INAD is an autosomal recessive conditio n that presents between the ages of 6 months and 3 years with truncal hypotonia, progres- s ive psychomotor delay, cerebellar ataxia, pyramidal signs, strabis- mus, nystagmus, and opt ic atrophy. Tetraparesis and progressive cognitive decline and seizure follow, with death t ypically in the fi rst decade (48). MRI demonstrates hypointensity of the globus pal- lidus (indicating iron accumulation) in addition to cerebellar atro- phy. Th e signal abnormalit y diff ers from the \200\230eye of the tiger \200\231 sign of PKAN as there is no central hyperintensity (49). loss, glio- sis, axonal spheroids, and iron deposition in the globus pal- lidus, red nucleu s, and substantia nigra. Th e HARP syndrome (hypo-prebetalipoproteinaemia, acanthocytosis, retinitis pigmen- tosa) is part of the PKAN spectrum. Neuropathological features include neuronal Th e diagnosis is suggested by MRI fi ndings of bilateral hyper- intense signal changes in the anteromedial globus pallidus with surrounding hypointensity in the globus pallidus and substantia nigra pars reticulata on T 2 -weighted images. Th is \200\230eye-of-the-tiger \200\231 sign is highly specifi c to PKAN. Most patients have mutations in the PANK2 gene ( 40, 41) and molecular analysis can confi rm the diagnosis. Atypical forms present later (2 \200\2237 years) with a picture of static encephalopathy an d later deterioration from 7 to 12 years, with progressive dystonia, ataxia, dysarthria, an d neurobehavioural dis- turbance (41). Again, MRI demonstrates iron accumulation in the med ial and lateral portions of the pallidum, and there may be EEG abnormalities. Both infantile and later forms of neuroaxonal dystrophy are caused by mutations in the PLA2 G6 gene, which encodes iPLA 2 -VIa, a calcium-independent phospholipase, which may disrupt mem- brane homeostasis (41, 48, 49). Treatment is symptomatic. Dystonia may occasionally benefi t from baclofen, trihexyphenidyl , or botulinum toxin. Bilateral pal- lidal stimulation and thalamotomy have also been used for intrac- table generalized dystonia in PKAN with evidence of sustained benefi t (42, 43) . A recent phase II trial of the oral iron-chelating drug deferiprone in ten patients with PKAN, demonstrated reduced pallidal iron content at 6 months as assessed by MRI T2* relaxom etry (44). However, there was no clinical change in dystonia or quality of life over the sa me period. It is possible that longer-term therapy, or earlier intervention, may aff ect ne urologi- cal progress. Two cases of Pakistani and Indian descent with dystonia \200\223 parkinsonism have also bee n found to have mutations in PLA2G6 (homozygous missense mutations) with an onset at 10 \200\22326 years of subacute dystonia \200\223parkinsonism, pyramidal signs, eye movement a bnormalities, and cognitive/psychiatric features (50). Cerebellar features which are presen t in typical INAD were absent in these cases. Also in contrast with INAD, iron was absent i n the basal gan- glia. Th ree individuals had good response to levodopa. Neuroferritinopathy Neuroferritinopathy is an adult-onset (mean age 40) autosomal dominant disorder which results in abnormal aggregates of iron Idiopathic basal ganglia calci \201 cation Idiopathic basal ganglia calcifi cation (Fahr \200\231s disease) is an auto- somal dominant neurodegenerative disease with basal ganglia CHAPTER 19 Other Dystonias 205 calcifi cation that typically presents between 30 and 50 years of age with chorea, dystonia , parkinsonism, ataxia, seizures, cognitive impairment, and neuropsychiatric disorder (51, 52). Pyramidal and cerebellar signs may also feature. It is slowly progressive. Over thirty aff ected families have been reported (53). sphingolipidoses the pathway of degradation of sphingolipids is dis- rupted, either by spec ifi c enzyme defi ciency or by lack of activator protein. Th is results in sphingolipid acc umulation in one or more organs, particularly the brain. Th e inheritance is autosomal rece s- sive in all these conditions except Fabry \200\231s disease and Pelizaeus \200\223 Merzb acher disease, which are X-linked. Calcifi cation of the globus pallidus, putamen, caudate, thalamus, and dentate nucleus is e vident on neuroimaging. Histopathology demonstrates perivascular iron deposits in the basal ganglia and dentate nucleus. A locus, IBGC1, has been identifi ed on chromo- some 14q (54) but the responsible gene has not been identifi ed. Treatment is symptomatic. Niemann \200\223Pick disease type C is described in detail below. Th e other lysosomal storage disorders are outlined in Table 19.2. Niemann \200\223Pick disease type C Niemann \200\223Pick disease type C is an autosomal rec essive lipid storage disease. Two-thirds of aff ected infants are of Ashkenazi Jewish par- entage. Prevalence in Europe is estimated as 1 in 150 000. Defective intracellular esterifi cation leads to the accumulation of free choles- terol in lysosymes. Th is causes a choles terol \200\230traffi c jam \200\231, possibly leading to a defi ciency in membrane cholest erol and resulting in membrane dysfunction in distal axons with subsequent apoptosis. Th er e is progressive neurological and hepatic dysfunction. Lysosomal storage disorders Th is is a large group of disorders including the gangliosidose s, neuronal ceroid lipofuscinosis (Batten \200\231s disease), the fucosi- doses, the leucod ystrophies, Niemann \200\223Pick disease type C, and Pelizaeus \200\223Merzbacher disease. All have systemic features but can also present with movement disorders, including dystonia . In the Table 19.2 Other lysosomal storage disorders which can cause dystonia Infantile and juvenil e forms Enzyme defect/ genetics -galactosidase gene Autosomal recessive Adult forms Pathology, diagnosis, prognosis GM1 gangliosidosis Early infantile form: hypotonia, failure to thrive, spasticity, macular cherry red spot, he patosplenomegaly, dysmorphic features, seizures, death during the second year Late infantil e and juvenile forms show slower progression Systemic features are uncommon Slowly progressive extrapyramidal features, dysarthria Dystonia is more common in adult ons et disease (55, 56) Usually no organomegaly or cherry-red spots Pathology: multilamellated neuronal inclusions primarily in the basal ganglia Macroscopic: widespread atrophy Diagnosis via vacuolated lymphocytes, foam cells in bone marrow and low -galactosidase in white cells or cultured \201 broblasts Prognosis: infantile has wors t outcome; death between 2 and 5 years of age GM2 gangliosidosis (a) Tay Sachs Autosomal recessive -hexosaminidase A subunit absent in white cells; highest carrier rat e in Ashkenazi Jews -hexosaminidase A and B subunits absent in white cells. Also a \200 ects non-Jewish infants Almost always evident by the fourth month Infantile form: hyperacusis/ abnormal startle, ps ychomotor regression, spasticity, seizures, macrocephaly, cherry-red spot, blindness Juveni le form: anterior horn cell disease, extrapyramidal signs intermittent psychosis As abov e but with hepatosplenomegaly Dystonia prominent Slowly progressive MND-type picture, tremor, dysarthria, intermittent ps ychosis (57) Pathology: megalencephaly, neuronal loss, reactive gliosis; nerve cells distended with glyc olipid. Inclusions preferentially located in anterior horn cells and the cerebellum in adul ts Enzymatic defect in serum, white blood cells, and cultured \201 broblasts from skin or amniotic \202 uid Prognosis: infantile has worst outcome: death between 2 and 5 years of age Untreatable but some states o \200 er screening to individuals of Jewish origin for t he recessive trait (b) Sandho \200 disease Metachromatic leukodystrophy Mutations in ASA/ARSA gene which encodes the lysosomal protein arylsulfatase A Manifests between the \201 rst and fourth year; progressive loss of motor and intellectua l functions; ataxia, optic atrophy, spasticity and seizures; death occurs by 5 years of age Juvenile cases: developmental regression, speech disturbance, ataxia, seizures, spastic qu adraparesis Adults: slow course of dementia, peripheral neuropathy, pyramidal signs, peripheral neuropa thy, seizures, ataxia Dystonia may occur in any form, typically late in the course of the d isease Pathology: demonstrates demyelination, metachromatic granule deposition in oligodendrocytes , macrophages, and neurons Diagnosis: de \201 ciency of arylsulfatase A activity in leucoc ytes or cultured \201 broblasts; molecular genetic testing for ARSA gene; increased urina ry excretion of sulfatides with absence of arylsulfatase Prognosis: late infantile form is fatal; otherwise in most cases there is progression to quadriplegic mute state over 1 \200 \2233 years; slower progression in late-onset cases. (Continued) Oxford Textbook of Movement Disorders 206 Table 19.2 (Continued) Enzyme defect/ genetics Galactocerebroside -galactosidase de \201 ciency Infantile and juvenile forms Adult forms Pathology, diagnosis, prognosis Krabbe disease (globoid cell leucodystrophy) Infantile onset >80% of cases Psychomotor regression, extreme irritability, recurrent pyrex ia of unknown origins, vomiting, seizures, sti \200 ness, opisthotonus, and spasms, periph eral neuropathy, optic atrophy, dystonia Adult-onset cases very rare Clinical features more variable and rate of progression may be slower Pathology: extensive demyelination and globoid cells throughout the white matter (globoid c ells are large histiocytes containing galactocerebroside) Diagnosis: enzyme de \201 ciency in leucocytes or cultured \201 broblasts Prognosis: death usually within 2 years Pelizaeus \200\223 Merzbacher disease Mutations of proteolipid protein gene mutations X-linked Manifests in \201 rst 3 months of life Dystonia, nystagmus titubation, hypotonia, stridor , tremor, choreoathetosis, psychomotor retardation, cognitive impairment, peripheral neurop athy, and later spastic quadriparesis and ataxia Milder late-onset cases: possible visual loss, are \202 exia, spastic paraparesis Neuropathology demonstrates central demyelination and axonal loss Diagnosis: direct mutatio n analysis Prognosis: most patients never walk or lose the ability in childhood or adolesce nce; may plateau in the second decade before subsequent psychomotor deterioration; some wit h later disease onset can survive to the sixth decade or longer Fucosidosis Alpha- l -fucosidase de \201 ciency, leading to accumulation of fucose-containing glycolip ids and oligosaccharides Numerous mutations of FUCA1 gene Mild to moderate psychomotor regression begins at 12 \200\22315 months, growth retardation, dysmorphism, excessive sweating, dysostosis multiplex, organomegaly, and angiokeratoma cor poris di \200 usum Rare: less than 100 cases, 20 of them in South Italy Diagnosis: abnormal enzyme activity in cultured \201 broblasts or leucocytes; electron mi croscopy: vacuoles in multiple tissues including brain and liver Prognosis: death can occur within 4 \200\2236 years; rare variant with slower progression into late childhood and adu lthood Presentation may be antenatally with fetal hydrops. Fift y per cent of cases present in the neonatal period with hypotonia, prolonged cholestatic jaundice, ascites, hepatosplenomegal y, or severe infi ltrative disease manifesting in liver and/or respiratory failure. Neurolo gical features emerge in infancy, late adolescence, or occasionally adulthood. Supranuclear gaze palsy (a hallmark of the condition), psychomotor regression, progressive dystonia, pr ogressive ataxia, spasticity, seizures, gelastic cataplexy, dysar- thria and dysphonia, and dysphagia have been described. A mac- ular cherry-red spot is evident in about a fourth of patients. Most infants die by the end of their second year due to an intercurrent infectio n. Adult cases are rare and are more likely to present with dementia or psychiatric symptom s (58). Later-onset cases die in the second to third decade and adult-onset cases progress more slowly. in the large pyramidal neurons, ballooned neurons in the basal ganglia and thalamus, axonal spheroids in the thalamus, brainstem, and cerebellum, and neurofi brillary tangles in the hippocampus, entorhinal cortex, thalamus, and basal ganglia in adults with the disease. Inborn errors of metabolism (Table 19.3) Lesch \200\223Nyhan syndrome Lesch \200\223Nyhan s yndrome is an X-linked recessive disorder caused by defi ciency of the purine salvage enzym e hypoxanthine-guanine phosphoribosyltransferase (HPRT) resulting in hyperuricaemia. Aff ec ted children appear normal at birth, but hypotonia and devel- opmental delay are evident by 3 \200\2236 months. Self-injurious behav- iour begins in the second year, followed by ment al retardation, extrapyramidal involvement (action dystonia, choreoathetosis, opisthotonos) , and pyramidal involvement (spasticity, hyper- refl exia, extensor plantar refl exes) (62) . Th e hallmark symptom is severe and involuntary self-mutilation (e.g. biting of lips and/ or fi ngers, head banging, eye-poking). Speech is delayed and dysar- thric. Limb dystonia i s universal and severe (62). Th ere may also be truncal dystonia with dystonic tremor and o pisthotonus, oroman- dibular and lingual dystonia (causing cheek- and lip-biting), and lary ngeal dystonia. Aff ected children may initially be diagnosed as having cerebral palsy and most never walk. Overproduction of uric acid and subsequent deposition of uric acid crystal s leads to gouty arthritis and nephropathy. Diagnosis is made by demonstration of abnormal cholesterol esterifi cation and fi lipin sta ining in cultured fi broblasts (59). Foam cells and sea-blue histiocytes can be demonstrate d in bone mar- row, spleen, liver, lung, lymph nodes, and tonsils, and inclusions seen in s kin biopsy. Diagnosis is confi rmed by demonstrating lipid traffi cking defects in cultured fi broblasts and should be followed by genotyping. Ninety-fi ve per cent of cases are caus ed by mutations in the NPC1 gene (18q11) which encodes a key protein in choles- terol traff i cking (60). Mutations in NPC2 (14q24.3) account for the remaining 5% of cases (61). Prena tal testing of cultured amniocytes or DNA is available. MRI of the brain may be normal initially but later shows marked atrophy of the cerebellum, cerebellar vermis, and corpus callosum. Neuropathological examination demonstrates lipids, particularly Diagnosis is suggested by the fi nding of hyperuricaemia. HPRT enzyme activity less than 1. 5% of normal in cells (e.g, blood, CHAPTER 19 Other Dystonias 207 Table 19.3 Other inborn errors of metabolism with motor phenotype including dystonia Mechanism Mutations in TPI which converts glyceraldehyde phosphate and dihydro-oxyacetone p hosphate Clinical course Age of onset, 2 years Chronic haemolytic anemia, dystonia, tremor, muscular atrophy secondary to anterior horn cell disease, corticospinal signs Death usually occurs in early childhood Diagnosis TPI levels in red blood cells Triosephosphate isomerase (TPI) de \201 ciency Aromatic amino acid decarboxylase (AADC) de \201 ciency Lack of AADC leading to reduced levels of biogenic amines dopamine, serotonin, noradrenalin e, and adrenaline Onset in \201 rst year Developmental delay, oculogyric crises, opisthotonic posturing, au tonomic dysfunction Bradykinesia, athetosis, myoclonic jerks, tongue-thrusting, \202 exor spasms Cognitive de \201 cits are variable Variable response to dopamine agonist or non-s elective MAOIs High plasma levels of levodopa and low levels of plasma dopamine and noradrenaline metaboli tes CSF: low levels of homovanillic acid and 5-hydroxyindoleacetic acid and elevated 3- O - methyldopa Direct genetic analysis is available on a research basis Glucose transportation defects Guanidinoacetate methyltransferase de \201 ciency, molybdenum co-factor de \201 ciency, a nd glucose transporter protein type 1 de \201 ciency may also exhibit dystonia as part of their clinical phenotypes cultured fi broblasts, lymphoblasts) is diagnostic. Sequence analysis of HPRT1 is also avai lable. general developmental delay. All are individually rare. Almost all these disorders are auto somal recessive. Management is symptomatic and includes the use of allopurinol (a xanthine oxidase inhibitor ) to reduce uric acid and thus the risk of nephrolithiasis, gouty arthritis, and tophi. How ever, this does not aff ect the development or severity of the neurobehavioural manifestati ons. Dystonia has been described in various other disorders of amino acid and organic acid metab olism, including methylmalonic aci- duria, 4-hydroxybutyric aciduria, 3-methylglutaconic ac idaemia, 2-oxoglutaric aciduria, and Hartnup disease. Measurement of serum and urinary amin o and organic acids is indicated in children with no other identifi able cause of dystonia. Amino and organic aciduria (Table 19.4) Disruption of the normal catabolism of amino acid o r organic acid pathways should be considered in any child presenting with an encephalopathy and metabolic acidosis, or in the child with more Mitochondrial disorders Leigh syndrome, or subacute necrotizing encephalomyelopathy, typica lly occurs as the result of mutations in the gene encoding Table 19.4 Amino and organic aciduria Disorder Glutaric aciduria type 1: mutations in the m itochondrial enzyme glutaryl-co-enzyme A dehydrogenase disrupt the metabolism of lysine, hy droxylysine, and tryptophan Clinical features Macrocephaly Subsequent encephalopathic crises (triggered by an intercurr ent febrile illness) Severe generalized dystonia is common choreoatheotosis, progressive extrapyramidal symptoms, spasticity and seizures, and a variable degree of intellectual im pairment Investigations Neuroimaging: frontotemporal atrophy; \200\230batwing \200\231 or \200\230 box-like \200\231 sylvian \201 ssures; often subdural e \200 usions or haematomas and re tinal hemorrhages Diagnosis: increased glutaric and 3-hydroxyglutaric acid in the urine; pl asma-free carnitine is reduced and glutaryl carnitine is elevated; reduced enzyme activity in \201 broblasts Pathology: neuronal loss and decreased GABA levels have been demonstrat ed in the putamen, caudate, and pallidum with striatal degeneration and spongiform white ma tter Management Newborn screening is used in some high-risk populations Identi \201 cation is c rucial before development of neurological signs Dietary restriction of lysine and tryptopha n, supplemented with l -carnitine and ribo \202 avin, prevents progression Supportive ther apy ( \202 uid, glucose, insulin repletion) during intercurrent infections Prognosis varie s: death in \201 rst decade during intercurrent illness or survival into adulthood Homocystinuria: cystathionine -synthase de \201 ciency Neurodevelopmental delay, often with behavioral problems, seizures in 20%, and extrapyramid al features Marfanoid habitus Osteoporosis and scoliosis Ectopia lentis Mild mental retarda tion Later thromboembolic vaso-occlusive disease Raised urinary homocysteine levels and abnormal plasma amino acid levels with elevated meth ionine and homocysteine and low cystine; con \201 rmation is via assay of cystathionine -synthase activity in \201 broblast culture Treatment with pyridoxine reduces/normalizes amino acid levels in up to 50%, may improve co gnition and delay onset of thromboembolic events, low methionine diet with cystine and b etaine supplementation Prognosis: increased risk of thromboembolic events (Continued) Oxford Textbook of Movement Disorders 208 Table 19.4 (Continued) Disorder Propionic acidaemia: propionyl CoA carboxylase de \201 cie ncy Clinical features Infants develop episodic severe metabolic acidosis and ketosis and enceph alopathy Surviving children subsequently have severe extrapyramidal movement disorders, sei zures, and developmental delay, thrombocytopenia, and neutropenia Investigations Diagnosis: measurement of organic acids and demonstration of a decrease in p ropionyl-CoA carboxylase in leucocytes or \201 broblasts Management Supportive care Frequent feeding Low-protein diet Acidotic crises treated with p rotein restriction, sodium bicarbonate, carnitine, and glucose Peritoneal dialysis may be r equired; carnitine and biotin supplementation Prognosis varies: neurological sequelae commo n despite treatment Methylmalonic aciduria: defective methylmalonyl CoA mutase Neonatal encephalopathy Erythematous rash Hepatomegaly Later developmental delay Nephritis with renal failure \200\230Metabolic stroke \200\231 (acute and chronic basal ganglia invo lvement) Choreoathetosis, dystonia, quadriparesis, pancreatitis, growth failure, functional immune impairment, optic nerve atrophy Analysis of organic acids in plasma and/ or urine Molecular genetic testing for de \201 ni tive diagnosis Intravenous administration of alkali and l -carnitine supplements in addition to high-dose vitamin B 12 during crises During periods of stability, diet should be low in the amino aci ds leucine, isoleucine, and valine Trinucleotide repeat disorders Dystonia can also feature as part of the movement disorder p henomenology encountered in Huntington \200\231s disease, spinoc- erebellar ataxias (3 and 17), and dentatorubral-pallidoluysian atrophy. SURF-1, which is important for cytochrome- c oxidase assembly. Other mitochondrial enzymati c abnormalities include defects in pyruvate dehydrogenase and respiratory complexes I, II, IV, and V (63). It may be inherited in a maternal, X-linked, or autosomal recessive fashion . Onset is typically acute or subacute in infancy or childhood, oft en following a viral in fection, with develop- mental regression, seizures, brainstem dysfunction, dystonia, ataxia , optic atrophy, and peripheral neuropathy. Abnormalities of ocular movement and respiratio n (e.g. episodic hyperventi- lation, apnoea) also feature. Death typically occurs by the ag e of 3 years. Th e diagnosis is supported by fi nding elevated levels of lactate and pyruva te in serum and CSF, an abnormal pattern of cytochrome- c oxidase expression on muscle biop sy, and an abnormal MRI signal and necrosis in the basal ganglia, thala- mus, and brainstem . It is confi rmed by molecular genetic testing. Treatment is supportive. Dystonia as a feature of other neurological conditions Parkinsonian disorders Dystonia is n ot uncommon in parkinsonism, including idiopathic Parkinson \200\231s disease (IPD), progre ssive supranuclear palsy, mul- tiple system atrophy, and corticobasal degeneration, in addi tion to X-linked dystonia \200\223parkinsonism and rapid-onset dystonia \200\223 parkinsoni sm described above. In IPD it features frequently during OFF periods in patients with Parkinson \200\231s disea se with motor fl uctuations, and it is also seen in patients with multiple system atrophy. Corticobasal degeneration classically features a dystonic hand or foot in addition to aprax ia and myoclonus; retrocollis of the neck is common in progressive supranuclear palsy (67). Dystonia is also common in autosomal recessive juvenile Parkinson disease. Leber \200\231s hereditary optic neuropathy Mutations in mitochondrial respiratory chain co mplexes I, III, or IV lead to this disorder, characterized by rapid bilateral pain- less vi sion loss beginning between ages 18 and 23 (63). Males are four times more frequently aff e cted than females. Transmission is maternal. Dystonia, ataxia, or spastic paraplegia may al so occur (64, 65). Th e diagnosis is supported by an elevated serum lactate and microangiop athic changes in the optic fundus. Direct DNA mutation analysis is available. Secondary dystonia Th e secondary forms of dystonia (Table 19.5) are typically caused by in jury to the basal ganglia and thalamus and include infarcts, tumors, vascular malformations , and trauma. Injury to cortical and brainstem structures and the cerebellum, spinal cord, and even peripheral nerves has also been associated with development of dystonia. Exposure to drugs and toxins can also cause either acute or chronic dystonia. Mohr \200\223Tranebjaerg syndrome (dystonia/deafness) Th is unusual disorder results from m utations in the genes encoding DDP1 or DDP2, proteins involved in mitochondrial transportat ion. It is inherited in a recessive X-linked fashion and is characterized by sensorineural hearing loss in early childhood, progressive dystonia (which usually develops in the teens) , cortical blindness, dysphagia, and paranoia (66). CHAPTER 19 Other Dystonias 209 Most reactions are idiosyncratic. Although less common than tardive dyskinesia, acute dysto nic reactions aff ect approximately 6% of patients exposed to \200\230typical \200\231 neu roleptics and 1 \200\2232% of those exposed to \200\230atypical \200\231 neuroleptics (78) . Risk factors for the devel- opment of acute dystonia include younger age, male sex, previ - ous occurrence of acute dystonia, recent cocaine use, race (white vs Asian), and presence of aff ective disorder. Craniocervical involvement is most common; oculogyria and jaw and neck dys- tonias are frequently painful. Symptoms spontaneously subside over hours. Table 19.5 Secondary causes of dystonia CNS tumor Vascular lesion Stroke Arteriovenous malformation Demyelination and in \202 ammatory Multiple sclerosis Central pontine myelinolysis Sj gren \200\231s syndrome Perinatal cerebral injury Cerebral palsy Kernicterus Infections Encephalitis (including viral and paraneoplastic) Abscess Subacute sclerosing panencephalit is Creutzfeldt \200\223Jakob disease Tardive dystonia is defi ned as chronic dystonia present for at least a month occurring eit her during or within 3 months of discontinu- ation of neuroleptic use. Other causes of seco ndary dystonia must be excluded, and there should be no family history of dystonia (79). Th e severity of dystonia does not correlate with the duration of exposure to the medication, and young males are particularly susceptible (80). Th e most frequently observed clinical picture is of retrocollis (but also torticollis) or opisthotonic trunk movements. However, spread is common with segmental or generalized dysto- nia in most patients. Trauma Head or cervical cord trauma Other Syringomyelia Arnold \200\223Chiari malformation Spinal stenosis Pachygyria Drugs and toxins See text Acute dystonic reactions usually respond quickly (within 20 min- utes) to intravenous antic holinergic drugs (e.g. diphenhydramine or benztropine). A subsequent short oral course of e ither drug is usually recommended to prevent recurrence. Tardive dystonia is oft en refract ory, although discontinuation of neuroleptics increases the chance of remission fourfold. M ore promisingly, pallidal DBS has been reported to improve symptoms of patients with tardiv e dystonia (81). Hemidystonia is one of the most common manifestations of sec- ondary dystonia associated wi th structural lesions (68), typically involving the caudate and the putamen (69 \200\22371) . In many of these cases, dystonia is accompanied by other movement disorders such as parki nsonism, chorea, and tics. Th e traditional view that dystonia arises only from basal ganglia injury has expanded to i nvolve other brain structures. Pathoanatomical correlates of hemidystonia have been identi- fi ed in the thalamus, the internal capsule, and the cortex, oft en in association with le sions of the basal ganglia (72). Th alamic lesions can cause limb dystonia, and the respons ible lesions occur most frequently in subnuclei linked to the cerebellum, not the basal gan glia (73). Further evidence points to cerebellar circuitry involvement (74). Structural les ions associated with cervical dys- tonia have most commonly localized to the brainstem and cer- ebellum, with fewer cases localizing to the cervical spinal cord and basal ganglia. In addition, structural and functional imaging studies link damage to the cerebellum or its c onnections to the emergence of dystonia (75). Prominent dystonia occurs in the spinocerebel lar ataxias, including some where the known neu- ropathology is limited to the cerebellum. Recently, abnormali- ties in cerebellothalamocortical pathways have been identifi ed in tor sinA DYT1 knock-in mice (76). Conclusions Th e clinical assessment and diagnosis of non-primary dystonias can be diffi cu lt, and are not helped by a rather cumbersome classi- fi cation system. Th e key point is t o determine whether dystonia is a major clinical feature, or just a more minor component of the phe- notype. Th e nature of the dystonia is also important; hemidystonia strongly sugg ests a contralateral basal ganglia lesion, whilst dysto- nia which worsens as the day progr esses points to dopa-responsive dystonia, which should never be missed as it is eminently t reatable. Indeed, all cases where there is predominant dystonia of young onset merit a ther apeutic trial of levodopa. Where dystonia is associated with other neurological features, a broader diff erential diagnosis is needed, which may be guided by family history or the pr esence of other features. Table 19.6 attempts to guide this process by summarizing syndromi c associations. Drug-induced dystonia Drug-induced dystonia may be of acute or delayed (tardive) onset and most commonly occurs with dopamine receptor blocking agents, such as neuroleptics (phenothi azines, butyrophenones, haloperidol, olanzapine, quetiapine) and antiemetics (metoclo- pram ide, prochlorperazine, promethazine). Agents which deplete dopamine, such as tetrabenazine, may also cause dystonia, and there are also reports of dystonia occurring with use of anti depres- sants (SSRIs, MAOIs), calcium antagonists, general anesthetic agents, anticonvulsan ts (carbamazepine, phenytoin), antimalarials, levodopa, ranitidine, ecstasy, and cocaine. Table 19.6 Clinical clues for diagnosing dystonia syndromes Features accompanying dystonia Ataxia peripheral neuropathy Condition Friedreich \200\231s ataxia Ataxia telangiectasia Niemann \200\223Pick type C Spinocerebell ar ataxia (e.g. SCA3) Metachromatic leucodystrophy Wilson disease Neuroacanthocytosis Acute dystonic reactions occur within hours or days of starting or rapidly increasing the d ose of antipsychotic medications (77). (Continued) Oxford Textbook of Movement Disorders 210 7. Ichinose H, Ohye T, Takahiashi E, et al. Hereditary progressive dysto- nia with marked d iurnal fl uctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994; 8 : 236 \200\2234 2. Table 19.6 (Continued) Features accompanying dystonia Dementia Condition 8. Furukawa Y, Guttman M, Sparagana SP, et al. Dopa-responsive dystonia due to a large dele tion in the GTP cyclohydrolase I gene. Ann Neurol 2000; 47 : 517 \200\2232 0 . Huntington \200\231s disease Spinocerebellar atrophy type 17 (SCA17) Creutzfeldt \200\223Ja kob disease PKAN Niemann \200\223Pick type C Neuroacanthocytosis 9. Maita N, Hatakeyama K, Okada K, Hakoshima T. Structural basis of biopterin induced inhib ition of GTP cyclohydrolase 1 by GFRP, its feed- back regulatory protein. J Biol Chem 2004; 279 : 51 524 \200\2234 0 . 10. Ludecke B, Knappskog PM, Clayton PT, et al. Recessively inherited L-DOPA-responsiv e pa rkinsonism in infancy caused by a point muta- tion (L205P) in the tyrosine hydroxylase gene . Hum Mol Genet 1996; 5 : 1023 \200\2238 . 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Neuron 2004; 43 : 169 \200\2237 5 . 27. Rodacker V, Toustrup-Jensen M, Vilsen B. Mutations Phe785Leu and Th r618Met in the Na + , K + ATPase, associated with familial rapid onset CHAPTER 19 Other Dystonias 211