BackgroundClassic galactosemia is an autosomal recessive disorder due to galactose‐1‐phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression.MethodsThirty‐three adults (mean age = 32.6 ± 11.7 years; range = 18–59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures.ResultsThe sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55–122). All subjects followed a dairy‐free diet and 75–80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10‐ year increment of age was associated with a twofold increase in odds of depression.ConclusionsTaken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

This study provides Class II evidence that varenicline improved the axial functions of gait, stance, and timed 25-foot walk but did not improve appendicular function, except for rapid alternating movements, in adult patients with genetically confirmed SCA3.

The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.

For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Spinocerebellar ataxia (SCA) is a neurodegenerative disorder caused by dysfunction of the cerebellum and its connected neural networks. There is currently no cure for SCA and symptomatic treatment remains limited. We aimed here to examine the effects of a repetitive transcranial magnetic stimulation (rTMS) targeting the cerebellum on clinical impression, postural control and gait in patients with SCA. In this randomized, double-blinded and sham-controlled study, 20 individuals aged 18–75 years with SCA confirmed by genetic testing completed rTMS or sham intervention comprising 20 sessions of MRI-guided stimulation over the cerebellum. Baseline assessments included the Standard Ataxia Rating Assessment (SARA), the 9-hole peg test of manual dexterity, the Timed Up-and-Go (TUG) test, standing postural control with eyes-open and eyes-closed, and gait. Immediate (within 1-week) and 1-month follow-ups were completed. Intervention compliance was high (19 ± 2 of 20 sessions) and no rTMS-related adverse events were reported. rTMS, compared to sham, was associated with greater percent improvement in SARA total score from baseline to the 1-month follow-up ( p = 0.008). Secondary analyses of individual SARA items revealed that rTMS improved performance within the “stance” sub-score only ( p = 0.002). This functional change was accompanied by improvement to several objective metrics of postural sway during eyes-open and eyes-closed standing ( p < 0.008). rTMS did not influence the 9-hole peg test, TUG, or gait kinematics. A 20-session rTMS intervention is safe and feasible for those with SCA. Additional research is warranted to confirm the observed longer-term benefits of this intervention on standing postural control. Clinical Trial Registration : www.ClinicalTrials.gov , identifier: NCT01975909

We describe a patient with a probable diagnosis of idiopathic late-onset cerebellar atrophy who shows improvement of limb coordination, speech and gait following 21 days of transcranial magnetic stimulation (TMS) applied to scalp regions presumably corresponding to the cerebellum. This case study provides, for the first time, a quantitative assessment of gait improvement in response to TMS therapy in ataxia, as well as neurophysiological evidence in support of modification of cerebello-cortical interaction that may underlie some of the improvements.

Introduction: Researchers hypothesized that in phenylketonuria (PKU) high brain phenylalanine (Phe) levels and low brain tyrosine (Tyr) levels affect neuropsychological functioning. However, traditional magnetic resonance spectroscopy (MRS) yielded uncertain results of brain Phe and could not adequately measure brain Tyr. This pilot study examined the potential of correlated spectroscopy (COSY) to quantify these biomarkers and explain variability in neuropsychological functioning.Methods: Nine adults with early treated classic PKU received magnetic resonance imaging (MRI) with COSY and a battery of neuropsychological tests. Brain Phe and Tyr in parietal white matter (PWM) were compared to results in gray matter of the posterior cingulate gyrus (PCG).Results: Brain Phe ranged from 101 to 182 (mean ¼ 136.76 AE 23.77) mmol/L in PCG and 76 to 185 (mean ¼ 130.11 AE 37.88) mmol/L in PWM. Brain Tyr ranged from 4.0 to 7.4 (mean ¼ 5.44 AE 1.01) mmol/L in PCG and 4.1 to 8.4 (mean ¼ 5.90 AE 1.48) mmol/L in PWM. Correlation coefficients were largest for brain Phe PWM and measures of auditory memory (rho ¼ À0.79), anxiety (rho ¼ 0.79), and executive functioning (rho ¼ 0.69). Associations were in the expected direction, with higher brain Phe and lower brain Tyr related to poorer functioning. The two participants with severe structural MRI abnormalities had low brain Tyr levels in PCG and 3/5 of the participants with moderate to severe MRI abnormalities had higher than average brain Phe levels.Conclusion: COSY has the potential to quantify brain Phe and Tyr at low concentrations and in specific brain regions. In this pilot study, these biomarkers were associated with indices of neuropsychological functioning. Additional studies are needed to validate the COSY results.

Classic galactosemia (OMIM# 230400) is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase deficiency. Newborn screening and prompt treatment with a galactose-free diet prevent the severe consequences of galactosemia, but clinical outcomes remain suboptimal. Five men and five women with classic galactosemia (mean age = 27.2 ± 5.47 years) received comprehensive neurological and neuropsychological evaluations, electroencephalogram (EEG) and magnetic resonance imaging (MRI). MRI data from nine healthy controls (mean age = 30.22 ± 3.52 years) were used for comparison measures. Galactosemia subjects experienced impaired memory, language processing, visual-motor skills, and increased anxiety. Neurological examinations revealed tremor and dysarthria in six subjects. In addition, there was ataxia in three subjects and six subjects had abnormal gait. Mean full scale IQ was 80.4 ± 17.3. EEG evaluations revealed right-sided abnormalities in five subjects and bilateral abnormalities in one subject. Compared to age-and gender-matched controls, subjects with galactosemia had reduced volume in left cerebellum white matter, bilateral putamen, and left superior temporal sulcus. Galactosemia patients also had lower fractional anisotropy and higher radial diffusivity values in the dorsal and ventral language networks compared