Entry - #605407 - SEGAWA SYNDROME, AUTOSOMAL RECESSIVE - OMIM
# 605407

SEGAWA SYNDROME, AUTOSOMAL RECESSIVE


Alternative titles; symbols

PARKINSONISM, INFANTILE, AUTOSOMAL RECESSIVE
DYSTONIA, DOPA-RESPONSIVE, AUTOSOMAL RECESSIVE
DOPA-RESPONSIVE DYSTONIA, AUTOSOMAL RECESSIVE
TYROSINE HYDROXYLASE DEFICIENCY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
11p15.5 Segawa syndrome, recessive 605407 AR 3 TH 191290
Clinical Synopsis
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Face
- Masked facies
Eyes
- Oculogyric crises
- Ptosis
NEUROLOGIC
Central Nervous System
- Dystonia
- Parkinsonism
- Rigidity
- Truncal hypotonia
- Limb dystonia
- Hypokinesia
- Motor delay
- Speech delay
- Gait ataxia
- Involuntary jerking movements
- Extrapyramidal symptoms
- Tremor
- Myoclonus (in 1 family)
- Autonomic symptoms
LABORATORY ABNORMALITIES
- Decreased CSF homovanillic acid (HVA)
- Decreased CSF 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)
- Normal CSF 5-HIAA
- Decreased activity of tyrosine hydroxylase
MISCELLANEOUS
- Onset in infancy or early childhood
- Variable severity
- Favorable response to L-DOPA
- See also autosomal dominant form (128230)
MOLECULAR BASIS
- Caused by mutation in the tyrosine hydroxylase gene (TH, 191290.0001).

TEXT

A number sign (#) is used with this entry because autosomal recessive Segawa syndrome is caused by homozygous or compound heterozygous mutation in the tyrosine hydroxylase gene (TH; 191290) on chromosome 11p15.

An autosomal dominant form of Segawa syndrome (128230) is caused by mutation in the GCH1 gene (600225).


Description

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).


Clinical Features

Ludecke et al. (1996) described an infant with jerky movements at the age of 3 months who developed generalized rigidity with very little spontaneous movement and continuing involuntary jerky movements. There was no diurnal variability in the symptoms. At the age of 6 months, the infant was noted to have an expressionless face, ptosis, drooling, and tremulous tongue movements. Tone in the limbs was variable and of the cogwheel type. Analysis of the cerebrospinal fluid (CSF) revealed a very low level of the dopamine metabolite homovanillic acid (HVA). Ocular instillation of phenylephrine led to dramatic improvement of the ptosis. Treatment with L-DOPA/cardidopa resulted in normalization of the CSF HVA and marked sustained improvement of the hypokinesia and other parkinsonian features. At the age of 3 years, the child was reported to have mild motor and speech delay with minimal gait ataxia.

Brautigam et al. (1998) and Wevers et al. (1999) reported 4 unrelated Dutch patients with Segawa syndrome. All had normal pregnancies and deliveries. Between 3 and 7 months of age, the children developed progressive severe motor retardation with predominant extrapyramidal symptoms. They appeared hypokinetic with masked facies, rigidity of the limbs, and truncal hypotonia. There was no diurnal fluctuation of symptoms. Treatment with L-DOPA resulted in marked clinical improvement.

Brautigam et al. (1999) reported an Italian boy, born of consanguineous parents, with a severe form of Segawa syndrome. He was born prematurely and showed severe respiratory distress in the perinatal period. From birth, he showed progressive hypotonia, dysphagia, hypokinesia, and reduced facial mimicry. He also had prolonged diurnal periods of lethargy with increased sweating alternative with irritability and rare sporadic dystonic movements. Brain MRI at age 5 months showed cerebral atrophy. CSF HVA was undetectable. Response to L-DOPA treatment was limited and not as favorable as reported in other patients with the disorder.

De Lonlay et al. (2000) reported a patient who met all diagnostic criteria for Segawa syndrome, including homozygosity for a new mutation in the TH gene. The patient had extrapyramidal symptoms, but other symptoms were atypical. Periodic neurologic episodes were observed every 4 days beginning at 18 months of age, and were unresponsive to treatment with L-DOPA. These episodes were marked by generalized hypertonia with opisthotonos and conjugate upward deviations of both eyes lasting several minutes, followed by severe hypotonia, poor contact, and excessive salivation and perspiration for several hours. CSF biochemical abnormalities were severe. Uncharacteristically, a strikingly abnormal urinary catecholamine metabolite pattern was also consistently observed. De Lonlay et al. (2000) concluded that the atypical presentation of this patient shows that the clinical and metabolic phenotype of TH deficiency is more variable than formerly thought, and that the condition should no longer be considered a treatable disorder per se.

Stamelou et al. (2012) reported a family in which 3 sibs had tyrosine hydroxylase deficiency. The mother was of British origin and the father was from Nigeria. The proband, who was described in detail, had severe hypotonia at age 6 months and never achieved motor milestones. She developed prominent and violent myoclonic jerks in all limbs, and dystonia in the upper limbs and face without diurnal variation. Treatment with levodopa at age 13 years resulted in marked improvement, and she learned to speak and drive an electric wheelchair. Cognition also improved and she attended school. At age 18 years, she had dystonic grimacing, dysarthria, generalized dystonia more prominent in the upper limbs, and action-induced myoclonus. There was no progression of symptoms over the next 9 years. EMG and EEG studies indicated a subcortical origin of the myoclonic jerks. Her 2 sibs had a similar phenotype, but showed better outcome than the proband because levodopa treatment was started earlier. Stamelou et al. (2012) noted that myoclonus was a major feature of the disorder in this family, suggesting that it should be considered part of the phenotypic spectrum of tyrosine hydroxylase deficiency.


Clinical Management

Dionisi-Vici et al. (2000) reported a child with severe tyrosine hydroxylase deficiency who had severe axial hypotonia and hypokinesia associated with dystonic and ballistic movements. L-DOPA therapy alone was unsuccessful, but a combination of low-dose L-DOPA and selegiline markedly improved the clinical picture. Haussler et al. (2001) reported a similar response.


Diagnosis

Brautigam et al. (1998) and Wevers et al. (1999) concluded that metabolic diagnosis of TH deficiency can only be made reliably by CSF measurement of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), metabolites of dopamine and norepinephrine, respectively. Decreased levels of these metabolites combined with normal 5-HIAA, the metabolite of serotonin, indicates a specific defect in tyrosine hydroxylase. Urinary measurements of these metabolites is not accurate. The authors noted that there is a steep rostral-caudal gradient for HVA and 5-HIAA in the CSF, as well as normal changes in values over the first months and years of life, and emphasized that standardized protocols and values are essential for correct diagnosis.


Mapping

In 6 families with a total of 7 children affected with Segawa syndrome, Ludecke et al. (1995) found linkage to a polymorphic repeat in intron 1 of the tyrosine hydroxylase gene on chromosome 11p.


Inheritance

The transmission pattern of Segawa syndrome in the family reported by Ludecke et al. (1995) was consistent with autosomal recessive inheritance.


Molecular Genetics

In a Caucasian family in which 2 children were affected with Segawa syndrome, Ludecke et al. (1995) demonstrated a homozygous point mutation in the TH gene (191290.0001). One sister and both parents were heterozygous for the mutation. Symptoms disappeared promptly after administration of a low dose of levodopa in combination with a decarboxylase inhibitor. Former generations were not affected, suggesting that this was an autosomal recessive form of the disorder. Knappskog et al. (1995) showed that the mutant enzyme found in the 2 sibs had reduced affinity for L-tyrosine, and that it had residual activity of about 15% of normal at substrate concentrations prevailing in vivo, which was considered to be compatible with the clinical phenotype.

In an infant with Segawa syndrome, Ludecke et al. (1996) identified a homozygous mutation in the TH gene (191290.0002). The parents were heterozygous for the mutation.

In 3 unrelated Dutch patients with Segawa syndrome, Brautigam et al. (1998) and Wevers et al. (1999) identified a homozygous mutation in the TH gene (R233H; 191290.0003). A fourth patient was compound heterozygous for R233H and a truncating deletion in the TH gene (191290.0009).

In an Italian boy with a severe form of Segawa syndrome, Brautigam et al. (1999) identified a homozygous mutation in the TH gene (191290.0011).

In affected patients from each of 2 families, Swaans et al. (2000) found compound heterozygosity for novel missense mutations in the TH gene as the basis of infantile-onset parkinsonism (see 191290.0004-191290.0007). All 4 patients were in the fourth decade of life at the time of report and had been able to live a normal life with low-dose L-DOPA medication for more than 30 years.

Verbeek et al. (2007) identified 3 different mutations in the promoter region of the TH gene (see, e.g., 191290.0010) in 7 patients with Segawa syndrome. The mutations all occurred within the highly conserved cAMP response element.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8600041, they identified a homozygous missense mutation in the TH gene (191290.0012) in 3 sibs with severe intellectual disability and a phenotype compatible with autosomal recessive Segawa syndrome. The parents, who were first cousins, had 3 healthy children.


REFERENCES

  1. Brautigam, C., Steenbergen-Spanjers, G. C. H., Hoffmann, G. F., Dionisi-Vici, C., van den Heuvel, L. P. W. J., Smeitink, J. A. M., Wevers, R. A. Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency. Clin. Chem. 45: 2073-2078, 1999. [PubMed: 10585338, related citations]

  2. Brautigam, C., Wevers, R. A., Jansen, R. J. T., Smeitink, J. A. M., de Rijk-van Andel, J. F., Gabreels, F. J. M., Hoffmann, G. F. Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin. Chem. 44: 1897-1904, 1998. [PubMed: 9732974, related citations]

  3. De Lonlay, P., Nassogne, M. C., van Gennip, A. H., van Cruchten, A. C., Billette de Villemeur, T., Cretz, M., Stoll, C., Launay, J. M., Steenberger-Spante, G. C. V., van den Heuvel, L. P. W., Wevers, R. A., Saudubray, J. M., Abeling, N. G. G. M. Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation. J. Inherit. Metab. Dis. 23: 819-825, 2000. [PubMed: 11196107, related citations] [Full Text]

  4. Dionisi-Vici, C., Hoffmann, G. F., Leuzzi, V., Hoffken, H., Brautigam, C., Rizzo, C., Steebergen-Spanjers, G. C., Smeitink, J. A., Wevers, R. A. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J. Pediat. 136: 560-562, 2000. [PubMed: 10753262, related citations] [Full Text]

  5. Haussler, M., Hoffmann, G. F., Wevers, R. A. L-dopa and selegiline for tyrosine hydroxylase deficiency. (Letter) J. Pediat. 138: 451-452, 2001. [PubMed: 11241071, related citations] [Full Text]

  6. Knappskog, P. M., Flatmark, T., Mallet, J., Ludecke, B., Bartholome, K. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum. Molec. Genet. 4: 1209-1212, 1995. [PubMed: 8528210, related citations] [Full Text]

  7. Ludecke, B., Dworniczak, B., Bartholome, K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum. Genet. 95: 123-125, 1995. [PubMed: 7814018, related citations] [Full Text]

  8. Ludecke, B., Knappskog, P. M., Clayton, P. T., Surtees, R. A. H., Clelland, J. D., Heales, S. J. R., Brand, M. P., Bartholome, K., Flatmark, T. Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. Hum. Molec. Genet. 5: 1023-1028, 1996. [PubMed: 8817341, related citations] [Full Text]

  9. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992, related citations] [Full Text]

  10. Stamelou, M., Mencacci, N. E., Cordivari, C., Batla, A., Wood, N. W., Houlden, H., Hardy, J., Bhatia, K. P. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 79: 435-441, 2012. [PubMed: 22815559, images, related citations] [Full Text]

  11. Swaans, R. J. M., Rondot, P., Renier, W. O., van den Heuvel, L. P. W. J., Steenbergen-Spanjers, G. C. H., Wevers, R. A. Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism. Ann. Hum. Genet. 64: 25-31, 2000. [PubMed: 11246459, related citations] [Full Text]

  12. Verbeek, M. M., Steenbergen-Spanjers, G. C. H., Willemsen, M. A. A. P., Hol, F. A., Smeitink, J., Seeger, J., Grattan-Smith, P., Ryan, M. M., Hoffmann, G. F., Donati, M. A., Blau, N., Wevers, R. A. Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. Ann. Neurol. 62: 422-426, 2007. [PubMed: 17696123, related citations] [Full Text]

  13. Wevers, R. A., de Rijk-van Andel, J. F., Brautigam, C., Geurtz, B., van den Heuvel, L. P. W. J., Steenbergen-Spanjers, G. C. H., Smeitink, J. A. M., Hoffmann, G. F., Gabreels, F. J. M. A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC). J. Inherit. Metab. Dis. 22: 364-373, 1999. [PubMed: 10407773, related citations] [Full Text]


Cassandra L. Kniffin - updated : 10/25/2012
Ada Hamosh - updated : 1/9/2012
Cassandra L. Kniffin - reorganized : 12/30/2003
Ada Hamosh - updated : 4/26/2001
Ada Hamosh - updated : 2/6/2001
Creation Date:
Ada Hamosh : 11/16/2000
alopez : 01/09/2024
carol : 09/20/2021
carol : 10/04/2016
mcolton : 02/24/2014
carol : 11/5/2012
ckniffin : 10/25/2012
carol : 1/9/2012
wwang : 12/11/2009
ckniffin : 11/23/2009
wwang : 4/4/2008
ckniffin : 3/20/2008
ckniffin : 3/20/2008
carol : 12/30/2003
ckniffin : 12/24/2003
cwells : 5/8/2001
alopez : 5/8/2001
terry : 4/26/2001
mcapotos : 2/12/2001
mcapotos : 2/8/2001
terry : 2/6/2001
carol : 11/17/2000
carol : 11/17/2000

# 605407

SEGAWA SYNDROME, AUTOSOMAL RECESSIVE


Alternative titles; symbols

PARKINSONISM, INFANTILE, AUTOSOMAL RECESSIVE
DYSTONIA, DOPA-RESPONSIVE, AUTOSOMAL RECESSIVE
DOPA-RESPONSIVE DYSTONIA, AUTOSOMAL RECESSIVE
TYROSINE HYDROXYLASE DEFICIENCY


SNOMEDCT: 715827001;   ORPHA: 101150;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
11p15.5 Segawa syndrome, recessive 605407 Autosomal recessive 3 TH 191290

TEXT

A number sign (#) is used with this entry because autosomal recessive Segawa syndrome is caused by homozygous or compound heterozygous mutation in the tyrosine hydroxylase gene (TH; 191290) on chromosome 11p15.

An autosomal dominant form of Segawa syndrome (128230) is caused by mutation in the GCH1 gene (600225).


Description

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).


Clinical Features

Ludecke et al. (1996) described an infant with jerky movements at the age of 3 months who developed generalized rigidity with very little spontaneous movement and continuing involuntary jerky movements. There was no diurnal variability in the symptoms. At the age of 6 months, the infant was noted to have an expressionless face, ptosis, drooling, and tremulous tongue movements. Tone in the limbs was variable and of the cogwheel type. Analysis of the cerebrospinal fluid (CSF) revealed a very low level of the dopamine metabolite homovanillic acid (HVA). Ocular instillation of phenylephrine led to dramatic improvement of the ptosis. Treatment with L-DOPA/cardidopa resulted in normalization of the CSF HVA and marked sustained improvement of the hypokinesia and other parkinsonian features. At the age of 3 years, the child was reported to have mild motor and speech delay with minimal gait ataxia.

Brautigam et al. (1998) and Wevers et al. (1999) reported 4 unrelated Dutch patients with Segawa syndrome. All had normal pregnancies and deliveries. Between 3 and 7 months of age, the children developed progressive severe motor retardation with predominant extrapyramidal symptoms. They appeared hypokinetic with masked facies, rigidity of the limbs, and truncal hypotonia. There was no diurnal fluctuation of symptoms. Treatment with L-DOPA resulted in marked clinical improvement.

Brautigam et al. (1999) reported an Italian boy, born of consanguineous parents, with a severe form of Segawa syndrome. He was born prematurely and showed severe respiratory distress in the perinatal period. From birth, he showed progressive hypotonia, dysphagia, hypokinesia, and reduced facial mimicry. He also had prolonged diurnal periods of lethargy with increased sweating alternative with irritability and rare sporadic dystonic movements. Brain MRI at age 5 months showed cerebral atrophy. CSF HVA was undetectable. Response to L-DOPA treatment was limited and not as favorable as reported in other patients with the disorder.

De Lonlay et al. (2000) reported a patient who met all diagnostic criteria for Segawa syndrome, including homozygosity for a new mutation in the TH gene. The patient had extrapyramidal symptoms, but other symptoms were atypical. Periodic neurologic episodes were observed every 4 days beginning at 18 months of age, and were unresponsive to treatment with L-DOPA. These episodes were marked by generalized hypertonia with opisthotonos and conjugate upward deviations of both eyes lasting several minutes, followed by severe hypotonia, poor contact, and excessive salivation and perspiration for several hours. CSF biochemical abnormalities were severe. Uncharacteristically, a strikingly abnormal urinary catecholamine metabolite pattern was also consistently observed. De Lonlay et al. (2000) concluded that the atypical presentation of this patient shows that the clinical and metabolic phenotype of TH deficiency is more variable than formerly thought, and that the condition should no longer be considered a treatable disorder per se.

Stamelou et al. (2012) reported a family in which 3 sibs had tyrosine hydroxylase deficiency. The mother was of British origin and the father was from Nigeria. The proband, who was described in detail, had severe hypotonia at age 6 months and never achieved motor milestones. She developed prominent and violent myoclonic jerks in all limbs, and dystonia in the upper limbs and face without diurnal variation. Treatment with levodopa at age 13 years resulted in marked improvement, and she learned to speak and drive an electric wheelchair. Cognition also improved and she attended school. At age 18 years, she had dystonic grimacing, dysarthria, generalized dystonia more prominent in the upper limbs, and action-induced myoclonus. There was no progression of symptoms over the next 9 years. EMG and EEG studies indicated a subcortical origin of the myoclonic jerks. Her 2 sibs had a similar phenotype, but showed better outcome than the proband because levodopa treatment was started earlier. Stamelou et al. (2012) noted that myoclonus was a major feature of the disorder in this family, suggesting that it should be considered part of the phenotypic spectrum of tyrosine hydroxylase deficiency.


Clinical Management

Dionisi-Vici et al. (2000) reported a child with severe tyrosine hydroxylase deficiency who had severe axial hypotonia and hypokinesia associated with dystonic and ballistic movements. L-DOPA therapy alone was unsuccessful, but a combination of low-dose L-DOPA and selegiline markedly improved the clinical picture. Haussler et al. (2001) reported a similar response.


Diagnosis

Brautigam et al. (1998) and Wevers et al. (1999) concluded that metabolic diagnosis of TH deficiency can only be made reliably by CSF measurement of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), metabolites of dopamine and norepinephrine, respectively. Decreased levels of these metabolites combined with normal 5-HIAA, the metabolite of serotonin, indicates a specific defect in tyrosine hydroxylase. Urinary measurements of these metabolites is not accurate. The authors noted that there is a steep rostral-caudal gradient for HVA and 5-HIAA in the CSF, as well as normal changes in values over the first months and years of life, and emphasized that standardized protocols and values are essential for correct diagnosis.


Mapping

In 6 families with a total of 7 children affected with Segawa syndrome, Ludecke et al. (1995) found linkage to a polymorphic repeat in intron 1 of the tyrosine hydroxylase gene on chromosome 11p.


Inheritance

The transmission pattern of Segawa syndrome in the family reported by Ludecke et al. (1995) was consistent with autosomal recessive inheritance.


Molecular Genetics

In a Caucasian family in which 2 children were affected with Segawa syndrome, Ludecke et al. (1995) demonstrated a homozygous point mutation in the TH gene (191290.0001). One sister and both parents were heterozygous for the mutation. Symptoms disappeared promptly after administration of a low dose of levodopa in combination with a decarboxylase inhibitor. Former generations were not affected, suggesting that this was an autosomal recessive form of the disorder. Knappskog et al. (1995) showed that the mutant enzyme found in the 2 sibs had reduced affinity for L-tyrosine, and that it had residual activity of about 15% of normal at substrate concentrations prevailing in vivo, which was considered to be compatible with the clinical phenotype.

In an infant with Segawa syndrome, Ludecke et al. (1996) identified a homozygous mutation in the TH gene (191290.0002). The parents were heterozygous for the mutation.

In 3 unrelated Dutch patients with Segawa syndrome, Brautigam et al. (1998) and Wevers et al. (1999) identified a homozygous mutation in the TH gene (R233H; 191290.0003). A fourth patient was compound heterozygous for R233H and a truncating deletion in the TH gene (191290.0009).

In an Italian boy with a severe form of Segawa syndrome, Brautigam et al. (1999) identified a homozygous mutation in the TH gene (191290.0011).

In affected patients from each of 2 families, Swaans et al. (2000) found compound heterozygosity for novel missense mutations in the TH gene as the basis of infantile-onset parkinsonism (see 191290.0004-191290.0007). All 4 patients were in the fourth decade of life at the time of report and had been able to live a normal life with low-dose L-DOPA medication for more than 30 years.

Verbeek et al. (2007) identified 3 different mutations in the promoter region of the TH gene (see, e.g., 191290.0010) in 7 patients with Segawa syndrome. The mutations all occurred within the highly conserved cAMP response element.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8600041, they identified a homozygous missense mutation in the TH gene (191290.0012) in 3 sibs with severe intellectual disability and a phenotype compatible with autosomal recessive Segawa syndrome. The parents, who were first cousins, had 3 healthy children.


REFERENCES

  1. Brautigam, C., Steenbergen-Spanjers, G. C. H., Hoffmann, G. F., Dionisi-Vici, C., van den Heuvel, L. P. W. J., Smeitink, J. A. M., Wevers, R. A. Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency. Clin. Chem. 45: 2073-2078, 1999. [PubMed: 10585338]

  2. Brautigam, C., Wevers, R. A., Jansen, R. J. T., Smeitink, J. A. M., de Rijk-van Andel, J. F., Gabreels, F. J. M., Hoffmann, G. F. Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin. Chem. 44: 1897-1904, 1998. [PubMed: 9732974]

  3. De Lonlay, P., Nassogne, M. C., van Gennip, A. H., van Cruchten, A. C., Billette de Villemeur, T., Cretz, M., Stoll, C., Launay, J. M., Steenberger-Spante, G. C. V., van den Heuvel, L. P. W., Wevers, R. A., Saudubray, J. M., Abeling, N. G. G. M. Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation. J. Inherit. Metab. Dis. 23: 819-825, 2000. [PubMed: 11196107] [Full Text: https://doi.org/10.1023/a:1026760602577]

  4. Dionisi-Vici, C., Hoffmann, G. F., Leuzzi, V., Hoffken, H., Brautigam, C., Rizzo, C., Steebergen-Spanjers, G. C., Smeitink, J. A., Wevers, R. A. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J. Pediat. 136: 560-562, 2000. [PubMed: 10753262] [Full Text: https://doi.org/10.1016/s0022-3476(00)90027-1]

  5. Haussler, M., Hoffmann, G. F., Wevers, R. A. L-dopa and selegiline for tyrosine hydroxylase deficiency. (Letter) J. Pediat. 138: 451-452, 2001. [PubMed: 11241071] [Full Text: https://doi.org/10.1067/mpd.2001.110776]

  6. Knappskog, P. M., Flatmark, T., Mallet, J., Ludecke, B., Bartholome, K. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum. Molec. Genet. 4: 1209-1212, 1995. [PubMed: 8528210] [Full Text: https://doi.org/10.1093/hmg/4.7.1209]

  7. Ludecke, B., Dworniczak, B., Bartholome, K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum. Genet. 95: 123-125, 1995. [PubMed: 7814018] [Full Text: https://doi.org/10.1007/BF00225091]

  8. Ludecke, B., Knappskog, P. M., Clayton, P. T., Surtees, R. A. H., Clelland, J. D., Heales, S. J. R., Brand, M. P., Bartholome, K., Flatmark, T. Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. Hum. Molec. Genet. 5: 1023-1028, 1996. [PubMed: 8817341] [Full Text: https://doi.org/10.1093/hmg/5.7.1023]

  9. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]

  10. Stamelou, M., Mencacci, N. E., Cordivari, C., Batla, A., Wood, N. W., Houlden, H., Hardy, J., Bhatia, K. P. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 79: 435-441, 2012. [PubMed: 22815559] [Full Text: https://doi.org/10.1212/WNL.0b013e318261714a]

  11. Swaans, R. J. M., Rondot, P., Renier, W. O., van den Heuvel, L. P. W. J., Steenbergen-Spanjers, G. C. H., Wevers, R. A. Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism. Ann. Hum. Genet. 64: 25-31, 2000. [PubMed: 11246459] [Full Text: https://doi.org/10.1017/S0003480000007922]

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Contributors:
Cassandra L. Kniffin - updated : 10/25/2012
Ada Hamosh - updated : 1/9/2012
Cassandra L. Kniffin - reorganized : 12/30/2003
Ada Hamosh - updated : 4/26/2001
Ada Hamosh - updated : 2/6/2001

Creation Date:
Ada Hamosh : 11/16/2000

Edit History:
alopez : 01/09/2024
carol : 09/20/2021
carol : 10/04/2016
mcolton : 02/24/2014
carol : 11/5/2012
ckniffin : 10/25/2012
carol : 1/9/2012
wwang : 12/11/2009
ckniffin : 11/23/2009
wwang : 4/4/2008
ckniffin : 3/20/2008
ckniffin : 3/20/2008
carol : 12/30/2003
ckniffin : 12/24/2003
cwells : 5/8/2001
alopez : 5/8/2001
terry : 4/26/2001
mcapotos : 2/12/2001
mcapotos : 2/8/2001
terry : 2/6/2001
carol : 11/17/2000
carol : 11/17/2000