Disease Information for Segawa Syndrome/Infant Parkinsonism

SEGAWA SYNDROME

. Background

Dopamine- or dopa-responsive dystonia (DRD), also known as hereditary progressive dystonia with diurnal variation (HPD), is an inherited dystonia typically presenting in the first decade of life. It is characterized by diurnal fluctuations, exquisite responsiveness to levodopa, and mild parkinsonian features. Segawa provided an early and detailed description (1976).

Nygard et al (1983) demonstrated linkage mapping of the autosomal-dominant DRD to chromosome 14q. In 1994, Ichinose et al identified the gene at the DRD locus in chromosome arm 14q to be responsible for the production of GTP cyclohydrolase I (GCH). Since the discovery of the gene mutation, many different mutations in the GCH 1 gene, TH gene (tyrosine hydroxylase), and SR (sepiapterin reductase) genes have been identified to cause levodopa responsive dystonic disorders, particularly of the autosomal recessive form of DRD.

Pathophysiology

TH activity and therefore tetrahydrobiopterin (BH4) production is high in the postnatal period, decreasing after infancy. The activity peaks during the first decade and progressively declines with age. The rate of decline in TH activity is marked initially, and then progresses until it reaches a plateau in the third decade.

Dopamine is produced from tyrosine by the action of TH, which uses BH4 as a cofactor. BH4 is also a cofactor for tryptophan and serotonin synthesis, and also for the enzyme nitrous oxide synthetase.

The first rate-limiting step for BH4 synthesis is GCH. The gene for GCH has been cloned to 14q 22.1-22.2 and is the gene responsible for autosomal-dominant DRD/HPD. (Others) mutations result in markedly reduced GCH values (2-20%), with a resultant decrease in dopamine content. Many cases of GCH 1 mutation negative have been discovered to harbor exon deletions in the GCH gene. A point mutation in the gene for TH has been shown to result in autosomal-recessive DRD. This mutation at the Gln 381 Lys locus in the tyrosine gene results in TH activity that is only 15% of normal (Lüdecke et al, 1995), with a resultant decrease in dopamine production.Sepiapterin reductase deficiency, by point mutation, has also been shown to have a similar yet somewhat more severe picture of dopa-responsive dystonia. Despite these advances, genetic testing is not definitive. Mortality/Morbidity

Marked gait difficulty (not uncommonly misdiagnosed as spastic diplegia or cerebral palsy) requiring wheelchair ambulation has been reported. No data are available on mortality associated with DRD, but patients surviving beyond the fifth decade with treatment have been reported. Autosomal recessive forms of DRD from TH deficiency and sepiapetrin deficiency show considerable motor and mental developmental delay with early mortality.

Race

Most cases have been reported from Japan, but an increasing number of reports are coming from other parts of the world. No clear racial predilection has been noted in European studies.

Sex

Females are involved more frequently than males, with a ratio varying from 2:1 to 4.3:1. The penetrance of GCH gene mutations is reported to be 2.3 times higher in females than in males (Furukawa et al, 1998).

Age

Typically, the onset is in the first decade of life (Chen et al, 1996; Nygaard, 1995), although it may present in the second to early third decades.

CLINICAL

The most common presenting symptom is a gait disturbance. These patients may be misdiagnosed as having cerebral palsy.

* Typically, the dystonia starts in one lower limb (with evening exacerbation) which results in a tiptoe walking pattern (equinus). Early in the disease course, patients are symptom free in the morning. Diurnal aggravation of symptoms depends more on the number of waking hours than on physical activity.

* The disease progresses markedly in the first 15 years, with postural dystonia progressing to all 4 limbs (even in the morning) by the end of the second decade. Progression slows in the third decade and plateaus thereafter (Segawa et al, 1986).

* Recently, variations in DRD clinical presentation have been described. These include trunk and focal dystonia such as spasmodic torticollis, oromandibular dystonia, and writer's cramp (Deona et al, 1997, Steinberger et al, 1999, Maruta et al, 1993).

* Clinical features described here are those characterized for dominant DRD with GCH1 gene mutations. Some of the TH-deficient patients have predominant parkinsonism features without diurnal fluctuations (Brautigam et al, 1998, Lüdecke et al, 1996, Furukawa and Kish, 1999).

Physical

The patient may have stunted growth with short stature if the disease was not treated in childhood. This improves if treatment is started early in the disease course. The dystonia is variable in severity, depending on the duration of disease prior to treatment.

* Gait disturbance is characterized by leg stiffness and a tendency to walk in an equinus posture. The great toe is dorsiflexed.

*

o Gait tends to worsen later in the day.

o With increasing age and without treatment, dystonia spreads to involve the trunk and all 4 extremities.

* Postural tremor, which is not observed in childhood, appears after the third decade. Resting tremor and rigidity are absent, and interlimb coordination is preserved (even in advanced cases).

* Bradykinesia may develop. This is not due to failure of initiation and poverty of movement as in parkinsonism; rather, it is due to failure of reciprocal innervation resulting from the dystonia.

* Muscle tone is increased and deep tendon reflexes are exaggerated (with ankle clonus). Plantar reflex is flexor, although striatal toe is common (Segawa et al, 1986).

* Clinical manifestations have significant heterogeneity, with intrafamilial variation in clinical phenotype, including the degree of levodopa responsiveness (Robinson et al, 1999).

DIFFERENTIALS

Ataxia with Identified Genetic and Biochemical Defects

Cerebral Palsy

Dopamine-Responsive Dystonia

Parkinson Disease

Parkinson Disease in Young Adults

Parkinson-Plus Syndromes

Progressive Supranuclear Palsy

Spasticity

Torticollis

Primarily dystonic juvenile parkinsonism (DJP)

Early onset idiopathic parkinsonism

Oromandibular dystonia

Focal dystonia

Cerebral palsy

Dystonia musculorum deformans

Dyspeptic dystonia with hiatal hernia (Sandifer syndrome)

Medication reactions (eg, phenothiazines, butyrophenones)

Metabolic diseases (eg, GM2 gangliosidosis, phenylketonuria, hypothyroidism, Leigh disease)

Lab Studies

* CBC with peripheral smear examination - To rule out acanthocytosis

* Serum for BUN, creatinine, liver function tests, copper, and ceruloplasmin

* Cerebrospinal fluid

*

o Cerebrospinal fluid (CSF) examination is not performed routinely, but some subjects may show significant reductions in CSF levels of neopterin and biopterin (Fujita and Shintaku, 1990).

o Measuring CSF pterins (Furukawa and Kish, 1999) may be useful in distinguishing the 3 disorders that are responsive to levodopa: GTPCH-deficient DRD (decreased biopterin and neopterin), TH-deficient DRD (normal biopterin and neopterin), and early onset parkinsonism (reduced biopterin and normal neopterin).

Imaging Studies

* Brain MRI may show abnormalities in the basal ganglia, suggesting Wilson or Hallervorden-Spatz disease. No specific abnormalities are seen in DRD.

* PET scan uptake of [18F]dopamine may be reduced in early onset Parkinson disease, but is normal in DRD (Snow et al, 1993; Sawle et al, 1991).

* Single-photon emission computed tomography (SPECT) with iodine I 123 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (b-CIT) can differentiate DRD (normal) from early onset Parkinson disease (reduced).

Other Tests

* Polysomnography in DRD shows a decreased number of twitch movements during REM sleep (~20% of normal). The ratio does not decrease with age, nor does it follow the decremental age variation and incremental nocturnal variation of healthy subjects (Segawa and Nomura, 1993).

* Phenylalanine loading test: Abnormality in phenylalanine metabolism has been useful in diagnosing DRD for most (50% of patients) but not all patients (Hyland et al, 1997; Saunders-Pullman et al, 1998).

*

o The basis for this test is that BH4 is required as a cofactor in the breakdown of phenylalanine to tyrosine.

o In DRD, BH4 deficiency results in accumulation of phenylalanine.

* Molecular biology: This can confirm the diagnosis in some cases (Furukawa et al, 1996).

Histologic Findings

In one autopsy case, the only neuropathologic finding was a decrease in melanin-pigmented neurons in the pars compacta of the substantia nigra.

[EMEDICINE Online 2008]

(Edit)