Whyte, Michael P.; McAlister, William H.; and et al, ,"Enzyme-replacement therapy in life-threatening hypophosphatasia." The New England Journal of Medicine.366,10. 904-913. (2012).

Background: Our Phase 2, open-label study of 11 infants and young children with lifethreatening perinatal or infantile hypophosphatasia (HPP) demonstrated 1-year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We report outcomes over ~7 years. Methods: Patients received asfotase alfa (1 mg/kg thrice weekly subcutaneously; adjusted to 3 mg/kg thrice weekly if required). HPP skeletal manifestations were evaluated on the Radiographic Global Impression of Change (RGI-C) scale (−3=severe worsening; +3=complete/near complete healing). Respiratory support, growth, and cognitive and motor function were also evaluated. Findings: Ten patients completed a 6-month treatment period and entered an extension; nine received asfotase alfa for ≥6 years and completed the study, with four treated >7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores ≥+2 at Years 6 and 7. No patient who completed the study required respiratory support after Year 4. Weight Z-scores improved to within normal range from Year 3 to study end; length/height Z-scores improved but remained below normal. Age-equivalent scores on Gross Motor, Fine Motor, and Cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. Treatment was generally well tolerated; adverse events were similar to those previously published. Interpretation: Patients with perinatal or infantile HPP treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralization. Respiratory function, growth, and cognitive and motor function also improved. Asfotase alfa is safe and effective in perinatal/infantile HPP.

Unilateral dorsal rhizotomies were done at the cervicothoracic and lumbosacral spinal cord levels in rats. In preliminary experiments dermatome maps were determined for the roots to be sectioned. The behavior of 37 rats was observed for many months after the rhizotomies. The rats with the dorsal roots sectioned in the cervicothoracic spinal cord exhibited the following behavior: at the border of the skin adjacent to the zone of deafferentation, the rat scratched vigorously and progressively denuded the skin; self-mutilation of varying degrees occurred in the deafferented limb. In some animals scratching occurred in the contralateral skin dermatome opposite to the partially deafferented zone. The rats with the dorsal roots sectioned at the lumbosacral level exhibited hypersensitivity to cutaneous stimulation but there was no scratching or self-mutilation. These results are discussed in the light of previous similar research.

We report the outcome of VLBWI born in a developing country with high resources. The rates of CLD, IVH and ROP were < or =25th percentile of the VON and mortality, NEC and PVL were in the 50th percentile.

Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.

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