Julia B. Hennermann

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

BACKGROUND Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. METHODS In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. FINDINGS Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. INTERPRETATION cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. FUNDING German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Eight-Year Follow-Up of Neuropsychiatric Symptoms and Brain Structural Changes in Fabry Disease.

Brain structural alterations and neuropsychiatric symptoms have been described repeatedly in Fabry disease, yet cognitive deficits have been shown to be only mild. Here, we aimed to investigate neuropsychiatric symptoms and brain structure longitudinally. We expected no clinically relevant increase of neuropsychiatric symptoms in parallel to increased brain structural alterations. We assessed 14 Fabry patients (46.1 ± 10.8 years) who had participated in our investigation eight years ago. Patients engaged in neuropsychiatric testing, as well as structural magnetic resonance imaging and angiography to determine white matter lesions, hippocampal volume, and the diameter of the larger intracranial arteries. While Fabry patients did not differ on cognitive performance, they showed progressive and significant hippocampal volume loss over the 8-year observation period. White matter lesions were associated with older age and higher white matter lesion load at baseline, but did not reach statistical significance when comparing baseline to follow-up. Likewise, intracranial artery diameters did not increase significantly. None of the imaging parameters were associated with the neuropsychiatric parameters. Depression frequency reduced from 50% at baseline to 21% at follow-up, but it did not reach significance. This investigation demonstrates clinical stability in cognitive function, while pronounced hippocampal atrophy is apparent throughout the 8 years. Our middle-aged Fabry patients appeared to compensate successfully for progressive hippocampal volume loss. The hippocampal volume decline indicates brain regional neuronal involvement in Fabry disease.

Timing of Cerebral Developmental Disruption in Molybdenum Cofactor Deficiency

In the April 2011 issue of the Journal of Child Neurology, Carmi-Nawi et al. reported a baby boy in whom, in a late pregnancy ultrasonographic investigation (after 35 weeks’ gestational age), ventriculomegaly and subcortical cysts were diagnosed. The child showed rapid deterioration after birth, with a dramatic increase in the brain destruction in postnatal imaging. Ultimately, the diagnosis of molybdenum cofactor deficiency was confirmed at 11 months of age and the child died shortly after. With a treatment option for molybdenum cofactor deficiency type A now on the horizon, the precise understanding of the temporal evolution of cerebral injury becomes extremely relevant. The reported case impressively underscores the broad variability in the presentation of this condition in late pregnancy and at birth. Although the reported child (and some of the historic cases discussed in the article) clearly showed focal cystic lesions in the subcortical white matter, the classic presentation of neuroimaging in the first days of life in this condition is that of acute edema mimicking hypoxic ischemic encephalopathy. The authors have so far started to treat seven newborns with molybdenum cofactor deficiency type A with cyclic pyranopterin monophosphate replacement therapy (unpublished results). The four infants who were investigated with magnetic resonance imaging in the first week of life showed not cysts but edema in their early scans (Figure 1). Given the dramatic acceleration of decay of the subcortical white matter after the cord is clamped, the rapid onset of clinical symptoms after birth and the fast clinical deterioration after birth, we would postulate that maternal-placental clearance of sulfite is quite effective until late pregnancy in the majority of cases. This hypothesis is further supported by the fact that most babies with molybdenum cofactor deficiency (all six of our patients) are born with normal head circumference, whereas postnatal head growth is minimal or absent in untreated patients. Although the early onset of seizures and the presence of cerebral edema is pointing toward some accumulation of sulfite prior to delivery, it seems for the above-named reasons unlikely that the

Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease

Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD.

Retinal and optic nerve degeneration in α-mannosidosis

Backgroundα-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor and hearing impairment, facial coarsening, and musculoskeletal abnormalities. Ocular pathologies reported previously were mainly opacities of the cornea and lens, strabismus, and ocular motility disorders. However, retinal and optic nerve degeneration have been rarely described.MethodsWe report ocular findings of 32 patients with α-mannosidosis. We particularly concentrated on retinal abnormalities which we supported by posterior segment examination, fundus photography, and Spectral-Domain optical coherence tomography (SD-OCT) imaging.ResultsTapeto-retinal degeneration with bone spicule formations in the peripheral retina or macular changes were seen in three patients (9.4%) on funduscopy; of these, two with optic nerve atrophy. Eight retinal images could be obtained by OCT or fundus photography; of these, six showed thinning of the outer retinal layers on OCT. Overall, optic nerve atrophy was seen in six patients (18.8%); of these, four with partial atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on funduscopy. Cataract was seen in two (6.3%), corneal haze also in two patients (6.3%). Six patients (18.8%) had manifest strabismus, four (12.5%) nystagmus, and in five patients (15.6%) impaired smooth pursuit eye movements were seen.ConclusionOcular pathologies are not exclusively confined to opacities of the cornea and lens or strabismus and ocular motility disorders but tapeto-retinal degeneration and optic nerve atrophy may be a common feature in α-mannosidosis. OCT technology helps detecting early outer retinal thinning which can progress with age and potentially leads to vision loss over time.

Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients

PURPOSE Main symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before. MATERIAL AND METHODS MRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS. RESULTS The deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132±24 vs. 177±6, BA/VA transition 113±21 vs. 152±13, right VA 108±23 vs. 156±13, left VA 110± 22 vs. 157±14 (all p<0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27±4 vs. 21±2, right VA 20±6 vs. 10±1, left VA 18±5 vs. 11±2 (all p<0.005). CONCLUSION MPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.