DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations.

OBJECTIVE: To report 4 novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization. METHODS: We screened 4 families including a total of 11 definitely affected members with a clinical picture resembling the original description. RESULTS: Four novel variants in the TUBB4A gene have been identified: D295N, R46M, Q424H, and R121W. In silico modeling showed that all variants have characteristics similar to R2G. The variants segregate with the disease in 3 of the families with evidence of incomplete penetrance in 2 of them. All 4 variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The hobby horse gait was evident in only 1 patient in this case series. CONCLUSIONS: Our interpretation is that laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.

H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?

Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.

Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal.

The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.

[A critical review of the problem of children at audiological and phoniatric risk in the first year of life]. / Revisione critica sul problema dei bambini a rischio audiologico e foniatrico nel primo anno di vita.

The "M. L. Marenzi" Centre of Infantile Otophoniatrics, in collaboration with the Department of Neonatal Pathology of the Fatebenefratelli Hospital in Milan, performed longitudinal controls of an audiological and phoniatric type in 252 children. In the present study attention is focused in particular on audiological evaluations made in a group of 71 infants aged from 6-9 months old. During audiological tests the evaluation of auditory capacity and the type of response to acoustic stimulus were taken into account. The behavioural observation of selective attention to sound is a very important index of the maturity of sensorial patterns. The retarded development of response to an acoustic stimulus may indicate future communication disorders. The type of response to acoustic stimulus obtained in 71 infants were compared with those in a further two groups of children: the first comprised 3822 children with no audiological risk, and the second 3755 children at audiological risk according to Feinmeser and Telly's expanded list. This comparison highlighted a significant persistence of an archaic-type response in the group of infants from the Department of Neonatal Pathology. It is therefore essential that these children are examined further from a phoniatric point of view.

[Laryngomalacia: a review of 42 cases]. / Laringomalacia: una revisión de 42 casos.

In the period from 1981 to 1990, in the Children's Hospital from Sevilla were performed 220 direct laryngoscopies and bronchoscopies to newborns and infants that showed as a main finding: stridor voice change or aspiration syndromes. In the 30 percent the main cause was a congenital laryngeal anomalies. Laryngomalacia is the most common congenital laryngeal anomaly with 42 cases. For it frequency, the otolaryngologist should be familiar with the clinical findings, diagnosis and actual management.

Ventral cleft of the larynx: a rare congenital laryngeal defect.

An anterior cleft of the larynx is apparently extremely rare. Only two patients with this defect have been reported in the American literature. The purpose of this paper is to present a child who was aphonic at birth and who was later found to have a congenital anterior cleft of the larynx. The diagnosis is established by the clinical symptoms, direct laryngoscopic examination, and radiographic studies. While severe voice change is the most prominent symptom of this defect, chronic aspiration is also a disquieting symptom, albeit controllable. The literature is reviewed, and the patient's symptoms and radiographic findings are documented. The clinical course over a period of almost 4 years is discussed.

[Ventral enclosure of the thyroid cartilage by the hyoid bone. A complex inhibition abnormality of the laryngeal structure]. / Die ventrale Umfassung des Schildknorpels durch das Zungenbein. Eine komplexe Hemmungsmissbildung des Kehlkopfskelettes.

Performing laryngeal CTs we identified a "ventral enclosure of the thyroid cartilage by the hyoid bone" in 3 patients with vocal disturbances and demonstrated for the first time the morphological and clinical characteristics of this complex inhibition malformation: --persistence of the embryonal close relation between the thyroid cartilage and the hyoid bone with normal position of the total larynx --feminine configuration of the thyroid cartilage --tendency to disturbances of growth of the thyroid cartilage with effect on the endolarynx --reduced vocal ability and predisposition to vocal disturbances.

[Urbach-Wiethe disease. Apropos of 2 cases]. / La maladie d'Urbach-Wiethe. A propos de deux observations.

The Urbach-Wiethe disease is a rare condition, where a hyaline substance of an unknown biochemical nature is accumulated in both teguments and mucous membranes. It has an autosomic and recessive genetic transmission. Cutaneous and mucous lesions (especially on the upper digestive tract) are described, insisting about the laryngeal location and the neurological troubles (with their main symptom: intracranial calcifications). The association of the disease with congenital indifference to pain is to be noted. Two particular cases are reported.

[Dysphonia in childhood]. / Dysphonie im Kindesalter.

Dysphonia can be found more often in childhood than in grown-up people. Disturbances of vocal purity occur at least at certain age levels in 23% of all children. Since dysphonia is the most important laryngeal symptom, it should be clarified exactly despite the difficulties of examination in children, in order to exclude tumours, which in most cases will be papillomas. For this purpose we developed a schema which includes not only subjective but also measuring and objective methods. The examples of congenital-inherited, congenital-acquired, non-congenital-inherited and non-congenital-acquired vocal disturbances show that there is a broad spectrum between the evaluation of the first cry, the right evaluation of numerous symptoms, the right evaluation of mutative dysphonias and the assessment of rhinophonias . In cases where it is not possible to clarify sufficiently well the causes of pathological vocal disorders by means of less complicated methods, it is advisable to employ the explained specific examination methods with objective documentation. The oto-rhino-laryngologist consulted by the parents of a child carries considerable responsibility also for the child's subsequent professional career if he is called upon to treat the patient's childhood dysphonia.

Voice change in the pediatric patient. A differential diagnosis.

This paper reviews the causes of voice change in the infant and child. Symptoms of dysphonia can be very early evidence of a serious problem, either within the larynx or resulting from a systemic disease. The need to investigate the cause of voice disturbances is stressed. The large number of diseases in which voice change occurs makes a complete examination of the child, both local and systemic, absolutely necessary in order to arrive at a specific diagnosis. The mechanism of voice change is described in each category of the numerous causes of dysphonia.