Search

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was, Patients with classical galactosemia frequently suffer from complications affecting the brain for which prognostic factors are lacking. In our cohort of classical galactosemia patients, we demonstrated a highly variable outcome, distinguished a subgroup of milder ‘variant patients’ and found an association between MRI abnormalities and lower intellectual outcomes and movement disorders., Graphical Abstract Graphical Abstract

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the ‘KE family’, who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene’s early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech. Electronic supplementary material The online version of this article (10.1007/s12311-018-0989-3) contains supplementary material, which is available to authorized users.

In spite of adequate dietary regimen, many patients with galactosemia have developmental abnormalities. We studied 8 patients with galactosemia, aged 9 months to 19 years who had all been treated with a galactose-free diet from an early stage. Neurological functioning, general developmental, and language and speech development were assessed in all cases. The results show that even medically well treated children and young adults with galactosemia are at risk to develop disabilities, including mental retardation, speech and language disabilities. Verbal dyspraxia was diagnosed in 3 of 6 patients, who had acquired verbal language, all with IQ 70 or below. This may indicate that verbal dyspraxia is just one symptom among others in patients with galactosemia and mental retardation.

Objective To describe specific language impairment in four children with velocardiofacial syndrome (VCFS). Design A descriptive, retrospective study of four cases. Setting University Hospital Groningen, tertiary clinical care. Patients Of 350 patients with cleft plate, 18 children were diagnosed with VCFS. Four children are described. Interventions In all children, cardiac and plastic surgery was carried out in the first year of life. Afterward, interventions consisted of hearing improvement, pharyngoplasty, and speech therapy. Main Outcome Inadequate and uncharacteristic development of articulation and expressive language in four children with VCFS were observed. They differed from the majority in two ways: their nonverbal IQ was in the normal range, and their language skills were below expectations for their IQ. Results Four of 18 patients with VCFS (22%) showed poor response to therapy and did not develop language in accordance with their normal learning abilities (nonverbal learning capacities and language comprehension). Persistent hypernasal resonance and severe articulation problems remained in all four children. In two children the expressive language profile was also not in agreement with the nonverbal profile: they produced only two- and three-word utterances at the age of 6.0 and 5.3 years. The other two children at the age of 6.8 and 6.4 years produced very long sentences, but they were unintelligible. Conclusions The speech and language impairment of the four children may be characterized as a phonological or verbal programming deficit syndrome and as such can be described as a specific language impairment in conjunction with VCFS.

Purpose: This study evaluates a genotype/phenotype relationship between developmental verbal dyspraxia (DVD) and the common, missense mutation of the galactose-l-phosphate uridyltransferase gene, Q188R, in patients with classic galactosemia (G/G). Methods: As part of this study, we devised a questionnaire for “speech problems” to be completed by the patient's clinician. To validate the questionnaire and determine its accuracy in detecting DVD, we analyzed questionnaire responses for 21 patients by testing them independently and directly for DVD through a speech pathologist blinded to the patients' genotype. Results: We found that the questionnaire had a sensitivity of 0.56 and a specificity of 0.75. We then calculated the prevalence of DVD for a larger set of 113 patients with G/G galactosemia whose biochemical phenotype, molecular genotypes, and clinical status were known. The prevalence of “speech problems” from raw data were 50 of 113 (44.2%). After adjusting for misclassification, 43 (38.1%) were classified as cases of DVD. Using multivariate, logistic, regression analyses we found a significant interaction between genotype and mean red blood cell (RBC) galactose-1-phosphate (Gal-1-P). When corrected, using mean RBC Gal-1-P > 3.28 mg%, the Q188R/Q188R genotype was the best predictor of DVD. There was a significant risk (odds ratio = 9.6, p = 0.0504) of having DVD associated with homozygosity for Q188R compared with other genotypes. Conclusions: We conclude that homozygosity for Q188R mutations in the GALT gene is a significant risk factor for DVD. However, poor metabolic control obviates this relationship as indicated by RBC Gal-1-P greater than 3.28 mg%.

Speech/language disorders are common in the fragile X syndrome. [Howard-Peebles, 1979: Am J Hom Genet 31:214-222; Renier et al., 1983: J Ment Defic Res 27:51-59; Sparks, 1984: Birth Defects and Speech-Language Disorders, pp. 39-43; Hanson et al., 1986: Am J Med Genet 23:195-206]. Verbal paraphasias have been considered a rare feature and word-finding difficulties have seldom been reported. Here we report on ten Brazilian patients who were evaluated for speech/language disturbances and found that word-finding difficulties were present in 50% of the cases, which is a slightly higher frequency than that of clear dyspraxia. We suggest, therefore, that word-finding difficulties and verbal dyspraxia can be a common feature within the spectrum of this syndrome. Additional speech findings are discussed.

The relationship between oral-stereognosis (O.S.) and the nature and severity of verbal dyspraxia was investigated in 16 post-C.V.A. dyspraxic patients. Scores for oral stereognosis were correlated with — (1) repetition of sounds and sentences in the Mayo Clinic Test of Verbal Dyspraxia (Darley, 1975); (2) words and phrases from Speech and Language Disturbances subtest of the Minnesota Test of Differential Diagnosis and Aphasia. In addition, subjects were assigned to one of four groups depending upon their presenting verbal symptoms, i.e., substitution; substitution and perseveration; substitution and initiation; and substitution, perseveration and initiation. Results indicated that O.S. scores correlated highly with the sounds and phrases subtests as well as with errors of substitution providing that the subject did not exhibit difficulties on initiation. Results were discussed in terms of the possible locus of brain lesion. Low scores on the O.S. test may indicate lesions to the post central kinesthetic...

The instrumental techniques of electropalatography and pneumotachography are used to examine details of tongue-palate contacts and VOT characteristics of three adult male subjects: two described as dysarthric and one as dyspraxic. A comparison is made between the subjects, and the results are compared with data from four normal speakers. The information is considered with reference to the neurological bases of these disorders of speech, and the advantages of an instrumental investigation over traditional auditory based assessments are exemplified. Some implications for therapy are also considered.

In 1861 Paul Broca described his patient “Tan” as having lost “the memory for the procedure one has to follow in order to articulate words”. This condition he called aphemia but subsequently it became known as Broca’s aphasia. Broca described a disorder in which the patient could understand spoken language, ideas were intact and he could recognize words and phrases which he could not pronounce nor repeat. Subsequent autopsy of Tan’s brain revealed a lesion in the area of the third convolution of the frontal left lobe (later designated Broca’s area). The features of this disorder parallel some of those associated with what later on became known as dyspraxia of speech or verbal dyspraxia. By annexing the word aphasia to Broca’s name a linguistic as against motoric connotation was apparent and this sparked off a volley of controversy which has been maintained with fervour ever since.