New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.

Effectiveness of asfotase alfa for treatment of adults with hypophosphatasia: results from a global registry.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. METHODS: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. RESULTS: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60-632 m) at baseline (n = 31) to 484 m at Month 12 (range 240-739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from - 0.72 (95% CI: - 1.23, - 0.21; n = 38) to - 1.13 (95% CI: - 1.76, - 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. CONCLUSIONS: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. REGISTRATION: NCT02306720; EUPAS13514.

The Global ALPL gene variant classification project: Dedicated to deciphering variants.

BACKGROUND: Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Variants of uncertain significance (VUS) cause diagnostic delay and uncertainty amongst patients and health care providers. RESULTS: The ALPL gene variant database (https://alplmutationdatabase.jku.at/) is an open-access archive for interpretation of the clinical significance of variants reported in ALPL. The database contains coding and non-coding variants, including single nucleotide variants, insertions/deletions and structural variants affecting coding or non-coding sequences of ALPL. Each variant in the database is displayed with details explaining the corresponding pathogenicity, and all reported genotypes and phenotypes, including references. In 2021, the ALPL gene variant classification project was established to reclassify VUS and continuously assess and update genetic, phenotypic, and functional variant information in the database. For this purpose, the database provides a unique submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the stringent ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature research including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing of variants in a co-transfection model to measure ALP residual activity. CONCLUSION: This classification project and the ALPL gene variant database will serve the global medical community, widen the genotypic and phenotypic HPP spectrum by reporting and characterizing new ALPL variants based on ACMG/AMP criteria and thus facilitate improved genetic counseling and medical decision-making for affected patients and families. The project may also serve as a gold standard framework for multidisciplinary collaboration for variant interpretation in other rare diseases.

Implicaciones en pediatría del primer consenso internacional para el diagnóstico y asistencia a pacientes con pseudohipoparatiroidismo y enfermedades relacionadas / Implication in Paediatrics of the First International Consensus Statement for the Diagnosis and management of pseudohypoparathyroidism and related disorders

Desde que en 1942 Albright y colaboradores describieran por primera vez el pseudohipoparatiroidismo como la existencia de hipocalcemia e hiperfosfatemia asociadas a resistencia tisular a la hormona paratiroidea (PTH) en presencia de una función renal normal, se han realizado grandes avances en la caracterización clínica y genética de los pacientes afectos de esta enfermedad. De hecho, no solo se han identificado las alteraciones moleculares responsables, sino que se ha podido establecer que variantes en otros genes de la misma vía de señalización, PTH/PTHrP a través de la proteína Gsα, son la causa de enfermedades que comparten determinadas manifestaciones clínicas con el pseudohipoparatiroidismo. En el ámbito pediátrico, los primeros síntomas o signos que deben hacernos pensar en alteraciones en esta vía son la presencia de osificaciones subcutáneas, la braquidactilia y/o la obesidad de inicio precoz, seguidas en el tiempo por la posible aparición de resistencia a la PTH. Esta sospecha clínica deberá ser confirmada mediante un diagnóstico molecular que permita el correcto seguimiento clínico coordinado y multidisciplinar. Entre los aspectos a tener en cuenta en la atención de estos pacientes se incluye la evaluación al diagnóstico y seguimiento de la eventual presencia de resistencia a la PTH y a la hormona tirotropa (TSH), deficiencia de hormona de crecimiento (GH), hipogonadismo, alteraciones esqueléticas, alteraciones de la salud dental, obesidad, resistencia a la acción de la insulina, intolerancia a la glucosa o diabetes mellitus tipo 2 e hipertensión, así como osificaciones ectópicas (subcutáneas o con afectación de tejidos más profundos) y alteración del desarrollo neurocognitivo

Since Albright and co-workers described pseudohypoparathyroidism in 1942 as the combined presence of hypocalcaemia and hyperphosphataemia associated with the existence of tissue resistance to parathyroid hormone (PTH) action upon normal renal function, great advances have been made in the clinical and genetic profile of patients affected by this condition. Furthermore, not only have genetic bases of pseudohypoparathyroidism been unravelled, but also variants in other genes involved in the PTH/PTHrP signalling pathway through Gsα, have been identified as the cause of diseases that share clinical features with pseudohypoparathyroidism. In the paediatric setting, the first symptoms suggesting the impairment of this signalling pathway are the presence of subcutaneous ossifications, brachydactyly and/or early onset obesity, followed by the possible development of PTH resistance. This clinical suspicion should be confirmed by an accurate molecular diagnosis to allow for coordinated multidisciplinary clinical management. Among the features of this group of disorders, physicians should pay attention to evaluation of PTH and/or thyrotropin (TSH) resistance at diagnosis and throughout follow-up, as well as growth hormone deficiency, hypogonadism, skeletal deformities, dental impairment, obesity, insulin resistance, impaired glucose tolerance or type 2 diabetes mellitus and hypertension, as well as ectopic ossifications (either subcutaneous or affecting deeper tissues) and impairment of neurocognitive development

Repuesta de los autores: Importancia de los factores socioeconómicos en estudios de obesidad / Authors Reply: The importance of socioeconomic factors in obesity studies

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La obesidad parental se asocia con la gravedad de la obesidad infantil y de sus comorbilidades / Parental obesity is associated with the severity of childhood obesity and its comorbidities

Introducción: La influencia de la obesidad parental sobre la de los hijos y sus comorbilidades, aunque asumida, está insuficientemente caracterizada. Pacientes y métodos: Estudio retrospectivo de 800 pacientes obesos (45,2% niñas; edad: 10,35 ± 3,40 años, índice de masa corporal [IMC]: + 4,22 ± 1,68 standard deviation score[SDS]). Se realizaron comparaciones entre grupos según la presencia de obesidad en ningún (n = 347) o algún progenitor (n = 453), diferenciando entre presencia de obesidad en el padre (n = 185), la madre (n = 151) o ambos progenitores (n=117). Variables consideradas: edad al inicio de la obesidad y en primera consulta, peso neonatal (PRN), IMC-SDS, glucemia, insulinemia, índice homeostatic model assessment (HOMA), colesterol total (CT), HDL, LDL, triglicéridos, 25-OH-vitamina D, área bajo la curva (AUC) de insulinemia en el test de tolerancia oral a la glucosa (TTOG), whole body insulin sensitivity index (WBISI), cocientes LDL/HDL y CT/HDL y reducción ponderal en los 12 primeros meses de seguimiento. Resultados: No hubo diferencias la distribución por sexo, etnia y pubertad entre grupos. Aquellos pacientes con algún progenitor obeso presentaron mayor PRN-SDS e IMC-SDS (p < 0,01), mayor afectación del metabolismo hidrocarbonado (insulinemia, AUC-insulina, HOMA, HbA1c [p < 0,01] y menor WBISI [p < 0,05]) que aquellos sin ningún progenitor obeso. Entre aquellos con un único progenitor obeso, se observó mayor PRN-SDS, insulinemia y HOMA y menor 25-OH-vitamina D (p < 0,05) cuando el antecedente era materno. Existía mayor prevalencia de síndrome metabólico cuando ambos progenitores eran obesos (chi2 = 5,96, p < 0,05). De todos ellos, 132 disminuyeron el IMC ≥ 1,5 SDS y/o el peso ≥10%, sin influencia del antecedente de obesidad parental. Conclusiones: La obesidad en algún progenitor determina mayor gravedad de la obesidad y de las alteraciones del metabolismo hidrocarbonado en sus hijos; acentuándose cuando la obesidad es materna o de ambos progenitores, pero sin influir en la posibilidad de éxito terapéutico

Introduction: The influence of parental obesity on their obese offsprings is acknowledged but insufficiently characterised. Patients and methods: Retrospective study of 800 obese patients (45.2% girls; age: 10.35 ± 3.40 years, body mass index [BMI]: + 4.22 ± 1.68 standard deviation score [SDS]). Group comparison according to the presence of obesity in none (n = 347) or any of the parents (n = 453), and then whether the obese parent was the father (n = 185), the mother (n = 151), or both parents (n = 117) were performed. The parameters analysed were: Age at the onset of the obesity and at their first visit, birth weight (BW), BMI-SDS, blood glucose, insulin level, homeostatic model assessment (HOMA) index, total cholesterol (TC), HDL, LDL, triglycerides, 25-OH-vitamin-D, area under the curve (AUC) for insulin in the oral glucose tolerance test (OGTT), whole body insulin sensitivity index (WBISI), LDL/HDL and TC/HDL ratios, and weight loss after 12 month follow-up. Results: No differences were observed between groups as regarding gender, ethnic background, or pubertal stage. Patients with one obese parent showed higher BW-SDS and BMI-SDS (P < .01), more severe impairment of carbohydrate metabolism (blood insulin, insulin-AUC, HOMA, HbA1c [P < .01] and lower WBISI [P < .05]) than those with no obese parent. Among those patients with a single obese parent, higher BW-SDS, insulin, HOMA, and lower 25-OH-vitamin D (P < .05) was observed when obesity was present in the mother. There was a higher prevalence of metabolic syndrome when both parents were obese (chi2 = 5.96, P < .05). A total of 132 patients reduced their BMI by ≥ 1.5 SDS, or their weight by ≥ 10%, with no influence of the background of parental obesity. Conclusions: Obesity in any parent determines a higher severity of their offspring obesity and metabolic comorbidities, more importantly when obesity is present in the mother or in both parents, but without interference in the options of therapeutic success

Influencia de la antropometría neonatal sobre las comorbilidades del paciente obeso / Influence of neonatal anthropometry on the comorbidities of the obese patient

Introducción: Los recién nacidos pequeños para su edad gestacional (PEG) presentan mayor riesgo de sufrir diversas enfermedades, tales como talla baja, obesidad infantil y sus comorbilidades metabólicas. Pacientes y métodos: Estudio de 883 pacientes obesos (47% niñas/53% niños; edad: 10,33 ± 3,32 años, IMC: +3,93 ± 1,42 SDS) con seguimiento prospectivo (5 años) del crecimiento para registro de talla adulta (n = 104). Se compararon al diagnóstico según hubiesen presentado antropometría neonatal adecuada (AEG; n = 810) o PEG (n = 73), las siguientes variables: edad en primera consulta, talla estandarizada (Z-score) respecto a talla diana, edad ósea, predicción de talla adulta, IMC estandarizado (Z-score), glucemia, insulinemia, HOMA, colesterol total, HDL, LDL, triglicéridos, 25-OH-vitamina D, área bajo la curva (AUC) de glucemia/insulinemia en el TTOG, cocientes LDL/HDL y CT/HDL y niveles de IGF-I e IGFBP-3. Resultados: Los pacientes nacidos PEG presentaban (a igualdad de edad, IMC-SDS, distribución étnica y puberal) una afectación más intensa del metabolismo lipídico (triglicéridos e índice triglicéridos/HDL superiores, ambos p<0,05) e hidrocarbonado (mayores niveles de glucemia, AUC de glucosa e insulina, HOMA, HbA1c y menor WBISI, todos p < 0,05), así como menores niveles circulantes de vitamina D (p < 0,05). Asimismo, presentaban un peor pronóstico de talla adulta con respecto a su talla diana (p < 0,01), pese a mostrar un grado similar de aceleración de la maduración esquelética y niveles comparables de IGF-I e IGFBP-3 que los AEG. Conclusiones: El antecedente de antropometría neonatal PEG se asocia a una mayor frecuencia e intensidad de alteraciones metabólicas y a un peor pronóstico de talla adulta en los niños y adolescentes obesos

Introduction: Small for gestational age (SGA) newborns show an increased risk of several diseases such as short stature, childhood obesity, and metabolic comorbidities. Patients and methods: The study included 883 obese patients (47% females/53% males; mean age: 10.33 ± 3.32 years, BMI: + 3.93 ± 1.42 SD), with prospective follow-up (5 years) of growth, recording adult height when achieved (n=104). Comparisons at diagnosis, according to their neonatal anthropometry; adequate for gestational age (AGA; n=810) vs. SGA (n=73), were performed for the following features: age at their first visit, standardised height for target height (Z-score), bone age, adult height prediction, BMI (Z-score), glycaemia, insulinaemia, HOMA, total cholesterol, HDL, LDL, triglycerides, 25-OH-vitamin D, area under the curve (AUC) for glucose and insulin in the OGTT, LDL/HDL and triglyceride/HDL ratio, insulin-like growth factor (IGF-I) and IGF-binding protein 3 (IGFBP-3) serum levels. Results: Despite similar BMI-SDS, ethnic, and pubertal distribution in both groups, patients with SGA showed more severe changes in lipid profile (triglyceride and triglyceride/HDL ratio, both P<.05) and carbohydrate metabolism (higher glycaemia, glucose and insulin AUCs, HOMA, HbA1c and lower whole-body insulin sensitivity index (WBISI), all P<.05) and lower 25-OH vitamin D levels (P<.05). They also showed a poorer adult height prediction (adjusted for target height) (P<.01), despite a similar degree of advance in skeletal maturation and similar IGF-I and IGFBP-3 levels than AGA patients. Conclusions: The background of SGA neonatal anthropometry is associated with a higher prevalence and severity of metabolic comorbidities and to a poorer adult height prediction in obese children and adolescents

Wind of change in pseudohypoparathyroidism and related disorders: New classification and first international management consensus / Vientos de cambio en pseudohipoparatiroidismo y enfermedades relacionadas: nueva clasificación y primer consenso internacional

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