Faculty Bibliography

Hypokalemia of renal origin can arise from genetic abnormalities in a variety of transporters or channel proteins that mediate tubular handling of potassium. Recently, mutations in claudin 10 have been documented in patients with hypokalemia in association with a range of other electrolyte abnormalities and skin and sweat gland manifestations. We report a 12-year-old Hispanic boy who presented with anhydrosis, aptyalism, alacrima, hypokalemia, and hypocalciuria, in whom we detected a homozygous mutation in the claudin 10 gene. During the 4-year follow-up period, he developed hypermagnesemia and a decline in estimated glomerular filtration rate to 59mL/min/1.73m². His unaffected parents and siblings were heterozygous for the mutation. We summarize the clinical phenotype encountered in patients with claudin 10 mutations. It is characterized by significant heterogeneity in electrolyte and extrarenal abnormalities and is associated with a risk for progressive loss of kidney function in up to 33% of cases. Awareness of this association between claudin 10 mutations and electrolyte abnormalities, namely hypokalemia and hypermagnesemia, sheds new light on the physiology of potassium and magnesium handling along the nephron and increases the likelihood of identifying the underlying tubular mechanism in patients with newly diagnosed hypokalemia with or without concomitant hypermagnesemia.

Introduction: Deep brain stimulation (

Objective: To assess the diagnostic yield of early-onset autonomicfailure in distinguishing the parkinsonian variant of multiple systematrophy from Parkinson's disease.
Method(s): Three-hundred and three patients with an MRI-supporteddiagnosis of multiple system atrophy-Parkinsonian (n = 71) orParkinson's disease (n = 232)-were retrospectively studied.According to their disease stage and duration at the time of cardiovascular autonomic function testing, patients were divided into earlydisease (Hoehn and Yahr stage\3 AND/OR disease duration\2 years) or advanced disease (Hoehn and Yahr stage C 3AND disease duration C 2 years) and features predictive of multiplesystem atrophy at last-available visit were investigated. A diagnosticprobability score was generated based on the discriminant variables inthe early disease group.
Result(s): In patients at early disease, the presence of orthostatichypotension (OR 6.50, 1.6-26.7 95% CI, p = 0.009), urinary disturbances (OR 22.1, 3.7-150.9 95% CI, p = 0.002) and posturalinstability (OR 27.9, 2.9-269.4 95% CI, p = 0.004) predicted multiplesystem atrophy at last-available visit. By assigning 1 point per abovementioned clinical feature, a cumulative probability score C 2 (scorerange 0-3) showed a 74.1% sensitivity and 90.1% specificity for afinal diagnosis of multiple system atrophy-Parkinsonian. Atadvanced disease, the presence of urinary disturbances (OR 3.0,1.0-8.7 95% CI, p = 0.05), but not of orthostatic hypotension, wasdistinctive of multiple system atrophy.
Interpretation(s): Autonomic failure featured both in Parkinson's disease and multiple system atrophy, but its early developmentanticipated a diagnosis of multiple system atrophy at follow-up.Parkinsonian patients presenting with 2 or more clinical features outof urinary disturbances, orthostatic hypotension or postural instabilitywithin the first 2 years of disease, have a high probability of sufferingfrom the parkinsonian variant of multiple system atrophy

Patients with hereditary sensory and autonomic neuropathy type III(HSAN III) exhibit marked gait disturbances. The cause of the gaitataxia is not known, but we recently showed that functional musclespindle afferents in the leg, recorded via intraneural microelectrodesinserted into the peroneal nerve, are absent in HSAN III, althoughlarge-diameter cutaneous afferents are intact. Moreover, there is atight correlation between loss of proprioceptive acuity at the knee andthe severity of gait impairment. Here we tested the hypothesis thatmanual motor performance is also compromised in HSAN III,attributed to the predicted absence of muscle spindles in the intrinsicmuscles of the hand. Manual performance in the Purdue pegboardtask was assessed in 12 individuals with HSAN III and 12 age-matched healthy controls. The mean (+/- SD) pegboard score (number ofpins inserted in 30 s) was 8.1 +/- 1.9 and 8.6 +/- 1.8 for the left andright hand respectively, significantly lower than the scores for thecontrols (14.3 +/- 2.9 and 15.5 +/- 2.0; P <0.0001). In five patients weinserted a tungsten microelectrode into the ulnar nerve at the wrist.No spontaneous or stretch-evoked muscle afferent activity could beidentified in any of the 11 fascicles supplying intrinsic muscles of thehand, whereas rich tactile afferent activity could be recorded from 4cutaneous fascicles. We conclude that functional muscle spindles areabsent in the hand, and likely absent in the long finger flexors andextensors, and that this largely accounts for the poor manual motorperformance in HSAN III

Hereditary sensory and autonomic neuropathy type III (HSAN III)features a marked ataxic gait that progressively worsens over time.We recently assessed whether proprioceptive disturbances can explainthe ataxia. Proprioception at the knee joint was assessed using passivejoint angle matching in 18 patients and 14 age-matched controls; fivepatients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to26/30. Patients with HSAN III performed poorly in judging jointposition at the knee: mean (+/- SE) absolute error was 8.7 +/- 1.0 andthe range was very wide (2.8-18.1); conversely, absolute error wasonly 2.7 +/- 0.3 (1.6-5.5) in the controls and 3.0 +/- 0.2 (2.1-3.4) in the cerebellar patients. This error was positively correlated tothe degree of ataxia in patients with HSAN III but not in patients withcerebellar ataxia. However, using the same approach at the elbowrevealed no significant differences in mean error in 12 patients withHSAN III (4.8 +/- 1.2; 3.0-7.2) and 12 age-matched controls(4.1 +/- 1.1; 2.1-5.5). Interestingly, microelectrode recordingsfrom the peroneal nerve showed a complete absence of spontaneousor stretch-evoked muscle afferent activity, confirmed in the ulnarnerve. Clearly, the lack of muscle spindles compromised proprioception at the knee but not at the elbow, and we suggest that patientswith HSAN III have learned to rely more on proprioceptive signalsfrom the skin around the elbow. Indeed, applying longitudinal stripsof elastic tape around the joint to increase tensile strain in the skinimproved proprioception at the knee but not the elbow