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Segawa syndrome, autosomal recessive

MedGen UID:
343087
Concept ID:
C1854299
Synonyms: Autosomal Recessive Infantile Parkinsonism; Dystonia, DOPA responsive, autosomal recessive; TH-Deficient Dopa-Responsive Dystonia; Tyrosine Hydroxylase Deficiency; Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): TH (11p15.5)
OMIM®: 605407

Disease characteristics

Excerpted from the GeneReview: Tyrosine Hydroxylase Deficiency
Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum. Based on severity of symptoms/signs as well as responsiveness to levodopa therapy, clinical phenotypes caused by pathogenic variants in TH are divided into (1) TH-deficient dopa-responsive dystonia (the mild form of TH deficiency), (2) TH-deficient infantile parkinsonism with motor delay (the severe form), and (3) TH-deficient progressive infantile encephalopathy (the very severe form). In individuals with TH-deficient dopa-responsive dystonia (DYT5b, DYT-TH), onset is between age 12 months and 12 years; initial symptoms are typically lower-limb dystonia and/or difficulty in walking. Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) may be present. In most individuals with TH-deficient infantile parkinsonism with motor delay, onset is between age three and 12 months. In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form. Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor). In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months. Fetal distress is reported in most. Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia, oculogyric crises, ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability. [from GeneReviews]
Authors:
Yoshiaki Furukawa  |  Stephen Kish   view full author information

Additional descriptions

From OMIM
Segawa syndrome is an autosomal recessive neurologic disorder characterized by onset in infancy of dopa-responsive dystonia. There are 2 main phenotypes: one is a severe complex encephalopathy apparent in the perinatal period, with diurnal fluctuations and autonomic disturbances, and the other shows a less severe course with onset in the first year of life of a progressive hypokinetic-rigid syndrome and generalized dystonia. The less severe type shows a better response to levodopa compared to the more severe type (summary by Stamelou et al., 2012). See also infantile parkinsonism-dystonia syndrome (613135), caused by mutation in the SLC6A3 gene (126455).  http://www.omim.org/entry/605407
From GHR
Dopa-responsive dystonia is a disorder that involves involuntary muscle contractions, tremors, and other uncontrolled movements (dystonia). The features of this condition range from mild to severe. This form of dystonia is called dopa-responsive dystonia because the signs and symptoms typically improve with sustained use of a medication known as L-Dopa.Signs and symptoms of dopa-responsive dystonia usually appear during childhood, most commonly around age 6. The first signs of the condition are typically the development of inward- and upward-turning feet (clubfeet) and dystonia in the lower limbs. The dystonia spreads to the upper limbs over time; beginning in adolescence, the whole body is typically involved. Affected individuals may have unusual limb positioning and a lack of coordination when walking or running. Some people with this condition have sleep problems or episodes of depression more frequently than would normally be expected.Over time, affected individuals often develop a group of movement abnormalities called parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability).The movement difficulties associated with dopa-responsive dystonia usually worsen with age but stabilize around age 30. A characteristic feature of dopa-responsive dystonia is worsening of movement problems later in the day and an improvement of symptoms in the morning, after sleep (diurnal fluctuation).Rarely, the movement problems associated with dopa-responsive dystonia do not appear until adulthood. In these adult-onset cases, parkinsonism usually develops before dystonia, and movement problems are slow to worsen and do not show diurnal fluctuations.  https://ghr.nlm.nih.gov/condition/dopa-responsive-dystonia

Clinical features

Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some CENTRAL NERVOUS SYSTEM DISEASES; (e.g., EPILEPSY, MYOCLONIC). Nocturnal myoclonus is the principal feature of the NOCTURNAL MYOCLONUS SYNDROME. (From Adams et al., Principles of Neurology, 6th ed, pp102-3).
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
Tremors are unintentional trembling or shaking movements in one or more parts of your body. Most tremors occur in the hands. You can also have arm, head, face, vocal cord, trunk, and leg tremors. Tremors are most common in middle-aged and older people, but anyone can have them. The cause of tremors is a problem in the parts of the brain that control muscles in the body or in specific parts of the body, such as the hands. They commonly occur in otherwise healthy people. They may also be caused by problems such as. -Parkinson's disease. -Dystonia. -Multiple sclerosis. -Stroke. -Traumatic brain injury. -Alcohol abuse and withdrawal. -Certain medicines. Some forms are inherited and run in families. Others have no known cause. . There is no cure for most tremors. Treatment to relieve them depends on their cause. In many cases, medicines and sometimes surgical procedures can reduce or stop tremors and improve muscle control. Tremors are not life threatening. However, they can be embarrassing and make it hard to perform daily tasks. NIH: National Institute of Neurological Disorders and Stroke.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting form degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Limb dystonia
MedGen UID:
152944
Concept ID:
C0751093
Sign or Symptom
A type of dystonia (abnormally increased muscular tone causing fixed abnormal postures) that affects muscles of the limbs.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
Impairment of the ability to coordinate the movements required for normal ambulation (WALKING) which may result from impairments of motor function or sensory feedback. This condition may be associated with BRAIN DISEASES (including CEREBELLAR DISEASES and BASAL GANGLIA DISEASES); SPINAL CORD DISEASES; or PERIPHERAL NERVOUS SYSTEM DISEASES.
Decreased CSF homovanillic acid
MedGen UID:
332501
Concept ID:
C1837626
Finding
Decreased concentration of homovanillic acid (HVA) in the cerebrospinal fluid. HVA is a metabolite of dopamine.
Parkinsonism with favorable response to dopaminergic medication
MedGen UID:
375989
Concept ID:
C1846868
Finding
No development of motor milestones
MedGen UID:
892432
Concept ID:
C4020874
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Muscular hypotonia of the trunk
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Mask-like facies
MedGen UID:
140860
Concept ID:
C0424448
Finding
A lack of facial expression often with staring eyes and a slightly open mouth.

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