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J Clin Invest 2021 May;131(9)

Institute of Human Genetics, University Hospital Jena, Friedrich Schiller University, Jena, Germany.

GDP-mannose-pyrophosphorylase-B (GMPPB) facilitates the generation of GDP-mannose, a sugar donor required for glycosylation. GMPPB defects cause muscle disease due to hypoglycosylation of α-dystroglycan (α-DG). Alpha-DG is part of a protein complex, which links the extracellular matrix with the cytoskeleton, thus stabilizing myofibers. Read More

Life (Basel) 2021 Feb 27;11(3). Epub 2021 Feb 27.

Department of Metabolic Biochemistry, Normandie University, UNIROUEN, CHU Rouen, INSERM U1245, 76000 Rouen, France.

NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. Read More

Rev Gastroenterol Mex (Engl Ed) 2020 Nov 27. Epub 2020 Nov 27.

Departamento de Gastroenterología, Hepatología y Nutrición Pediátrica, Unidad de Procedimientos, Yale University School of Medicine, New Haven, Connecticut, Estados Unidos.

Endocr Metab Immune Disord Drug Targets 2021 ;21(3):534-543

Department of Oncologic and Urologic Surgery, the 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, Zhejiang Province, China.

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed.

Methods: This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported. Read More

Hormones (Athens) 2021 Mar 22;20(1):197-205. Epub 2020 Jul 22.

Department of Endocrinology, PGIMER, Chandigarh, 160012, India.

Introduction: Triple A (Allgrove) syndrome is a rare autosomal recessive disorder characterized by cardinal features of primary adrenal insufficiency (AI) due to adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrima. It is frequently associated with neurological manifestations such as autonomic dysfunction, cognitive dysfunction, cranial nerve, or motor involvement. Amyotrophy/motor neuron disease is a rare association. Read More

Arch Soc Esp Oftalmol (Engl Ed) 2021 Jan 27;96(1):48-51. Epub 2020 Jun 27.

Servicio de Oftalmología, Hospital Marina Baixa, Villajoyosa, Alicante, España.

The purpose of this report is to describe a case of a unilateral congenital absence of the lacrimal gland in a 7-year-old girl with ocular symptoms, no tear production and a conjunctival tumour at the supero-external angle of the right eye. The visual acuity was 20/20 in both the eyes. The right eye showed mucous secretion, corneal erosions and filaments. Read More

Ophthalmic Plast Reconstr Surg 2020 Nov/Dec;36(6):e154-e156

Department of Ophthalmology, Sussex Eye Hospital, Brighton and Sussex Foundation NHS Trust, Brighton, United Kingdom.

Acquired unilateral alacrima as a presenting sign of an intracranial tumor is exceptionally rare, and only described once previously in a case of nasopharyngeal carcinoma. The authors present a 32-year-old female patient who presents with a year-long history of alacrima and arhinorrhea. She was subsequently diagnosed with a petroclival chondrosarcoma extending into Meckel's cave and the cavernous sinus and underwent surgical debulking. Read More

JIMD Rep 2020 May 10;53(1):2-9. Epub 2020 Apr 10.

Metabolic Diseases Unit, Pediatric Department, Santa Maria's Hospital - Lisbon North University Hospital Center EPE, Pediatric University Clinic, Faculty of Medicine, University of Lisbon Lisbon Portugal.

Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non-consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. Read More

Am J Med Genet A 2020 06 10;182(6):1426-1437. Epub 2020 Apr 10.

Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. Read More

Hum Mol Genet 2020 06;29(10):1635-1647

Takeda-CiRA Joint Program (T-CiRA), Kanagawa 2518555, Japan.

N-glycanase 1 (NGLY1) deficiency, an autosomal recessive disease caused by mutations in the NGLY1 gene, is characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, movement disorders and other neurological phenotypes. Because of few animal models that recapitulate these clinical signatures, the mechanisms of the onset of the disease and its progression are poorly understood, and the development of therapies is hindered. In this study, we generated the systemic Ngly1-deficient rodent model, Ngly1-/- rats, which showed developmental delay, movement disorder, somatosensory impairment and scoliosis. Read More

Cornea 2020 Jun;39(6):782-783

Department of Ophthalmology, Centre Hospitalier Universaite Sainte-Justine, Montreal, QC, Canada; and.

Purpose: To report 2 novel variants in the AAAS gene consistent with the diagnosis of Allgrove syndrome.

Methods: A 12-year-old girl was referred to our clinic for progressive bilateral decrease in visual acuity. She was known for achalasia that had been surgically treated at a very early age. Read More

JIMD Rep 2020 Jan 30;51(1):82-88. Epub 2020 Jan 30.

Department of Pediatrics, Nutrition and Metabolic Diseases The Children's Memorial Health Institute Warsaw Poland.

Objectives: Together with the lysosomal storage diseases, NGLY1 deficiency is a congenital disorder of deglycosylation (NGLY1-CDDG). Since the first report in 2012, 26 patients have been described. All but one were diagnosed by exome or genome sequencing; the remaining one was identified by finding an increased concentration of an urinary marker. Read More

AACE Clin Case Rep 2019 Nov-Dec;5(6):e357-e361. Epub 2019 Aug 15.

Objective: Allgrove syndrome (AS), also known as triple-A syndrome, is a rare disorder characterized by alacrima, achalasia, adrenal insufficiency, and other manifestations such as problems related to growth, puberty, and neuropsychological development. Although the genetics of this disorder have been studied extensively in recent decades, clinical information is still lacking.

Methods: We present a unique case of AS from which we have gained significant insight into its clinical course, especially the management of hypoglycemia. Read More

J Hum Genet 2020 Apr 21;65(4):387-396. Epub 2020 Jan 21.

Department of Hepatology, Children's Hospital of Fudan University, 399 Wanyuan Road, 201102, Shanghai, China.

NGLY1 deficiency is the first and only autosomal recessive congenital disorder of N-linked deglycosylation (NGLY1-CDDG). To date, no patients with NGLY1 deficiency has been reported from mainland China or East Asia in English literature. Here, we present six patients with a diagnosis of NGLY1-CDDG on the basis of clinical phenotype, genetic testing, and functional studies. Read More

J Endocrinol Invest 2020 Jul 14;43(7):973-982. Epub 2020 Jan 14.

Dipartimento di Scienze Cliniche e di Comunità, Division of Endocrine and Metabolic Diseases and Lab. of Endocrine and Metabolic Research, Dipartimento di Medicina Endocrino-Metabolica, Università degli studi di Milano, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milano, Italy.

Purpose: The triple A syndrome (AAAS) is an inherited condition associated with mutations in the AAAS gene, which encodes a protein of 546 amino acids known as ALADIN (alacrima achalasia adrenal insufficiency neurologic disorder) whose function is not well understood. This protein belongs to the WD-repeat family of regulatory proteins and is located in the nuclear pore complexes. Only a few cohorts of AAAS patients have been reported and fully characterized. Read More

Am J Med Genet A 2020 03 3;182(3):425-430. Epub 2020 Jan 3.

Rare Disease Institute, Children's National Health System, Washington, District of Columbia.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of inborn errors of metabolism mostly causing multisystem disease. In 2013, biallelic mutations in the GMPPA gene were described in association with one such CDG known as alacrima, achalasia, and mental retardation syndrome (AAMR). To date, 18 patients have been reported, nearly all displaying the same pathognomonic triad of symptoms described in the name. Read More

Cell Rep 2019 12;29(13):4620-4631.e4

Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

Patients with pathogenic mutations in NGLY1 cannot make tears and have global developmental delay and liver dysfunction. Traditionally, NGLY1 cleaves intact N-glycans from misfolded, retrotranslocated glycoproteins before proteasomal degradation. We demonstrate that Ngly1-null mouse embryonic fibroblasts, NGLY1 knockout human cells, and patient fibroblasts are resistant to hypotonic lysis. Read More

Am J Med Genet A 2020 03 11;182(3):570-575. Epub 2019 Dec 11.

Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center Göttingen, Göttingen, Germany.

Cohen syndrome (CS) is a rare autosomal recessive disorder associated with mutations in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. The core clinical phenotype comprises a characteristic facial gestalt, marked developmental delay, and myopia. Additional, nonobligatory features include obesity, microcephaly, short stature, muscular hypotonia, scoliosis, narrow hands and feet, progressive retinopathy, as well as neutropenia. Read More

Pediatric Health Med Ther 2019 29;10:99-106. Epub 2019 Aug 29.

Department of Pediatrics, NewYork-Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, USA.

Allgrove syndrome or triple A (3A) syndrome is a multisystem disorder which classically involves the triad of esophageal achalasia, alacrima, and adrenal insufficiency due to adrenocorticotropin hormone insensitivity. It follows an autosomal recessive pattern of inheritance and is associated with mutations in the (achalasia-addisonianism-alacrima syndrome) gene. Since its first description in 1978, the knowledge on clinical and genetic characteristics has been expanding; however, the current literature is limited to case reports and case reviews. Read More

J Endocrinol Invest 2020 Feb 21;43(2):185-196. Epub 2019 Aug 21.

Department of Pediatric Endocrinology and Diabetes, Marmara University, Ministry of Health, Pendik Training and Research Hospital, Istanbul, Turkey.

Background: Allgrove syndrome (OMIM 231550) is a rare autosomal recessive disease characterized by non-CAH primary adrenal insufficiency (non-CAH PAI), alacrima, and achalasia. It is caused by mutations in the AAAS gene. The syndrome is also associated with variable progressive neurological impairment and dermatological abnormalities. Read More

Eur J Med Genet 2019 Jul 6;62(7):103665. Epub 2019 May 6.

Children's Hospital, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Triple A syndrome, a multisystemic autosomal recessive disease, is characterized by the clinical triad of adrenal insufficiency, alacrima and achalasia in combination with progressive neurological impairments. The disorder is caused by homozygous or compound heterozygous mutations in the AAAS gene. Here we present the clinical and molecular data of a ten year old patient with triple A syndrome. Read More

Cold Spring Harb Mol Case Stud 2019 06 3;5(3). Epub 2019 Jun 3.

Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg 413 45, Sweden.

β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is caused by mutations in and is extremely rare in humans. Although the clinical presentation is heterogeneous, common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections. Read More

J Steroid Biochem Mol Biol 2019 05 25;189:73-80. Epub 2019 Feb 25.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, United Kingdom. Electronic address:

Hereditary adrenocorticotropin (ACTH) resistance syndromes encompass the genetically heterogeneous isolated or Familial Glucocorticoid Deficiency (FGD) and the distinct clinical entity known as Triple A syndrome. The molecular basis of adrenal resistance to ACTH includes defects in ligand binding, MC2R/MRAP receptor trafficking, cellular redox balance, cholesterol synthesis and sphingolipid metabolism. Biochemically, this manifests as ACTH excess in the setting of hypocortisolaemia. Read More

Hormones (Athens) 2019 Mar 5;18(1):109-112. Epub 2019 Jan 5.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, 10 Center Drive, Building 10, Room 1-3330, Bethesda, MD, 20892, USA.

Objective: Triple A syndrome is a rare autosomal recessive disorder caused by mutations in the AAAS gene on chromosome 12q13. Its main clinical features are alacrima, achalasia, and adrenal insufficiency, with most patients also having neurological symptoms and autonomic dysfunction. The neurologic manifestations are less well-understood, especially in children. Read More

Clin Ophthalmol 2018 11;12:2591-2595. Epub 2018 Dec 11.

Department of Ophthalmology, Kyorin University School of Medicine, Tokyo 181-8611, Japan,

Objectives: It is often hard to reach a definitive diagnosis of congenital alacrima because of the difficultly in proving the lack of lacrimal tissue. We report here the distinct tear protein profile in presumed congenital alacrima.

Patients And Methods: A 13-year-old girl with presumed congenital alacrima and 15 healthy volunteers aged 23-35 years were included in this study. Read More

Physiother Theory Pract 2020 Sep 3;36(9):1035-1042. Epub 2018 Dec 3.

Rusk Rehabilitation, Clinical Instructor, Department of Rehabilitation Medicine NYU School of Medicine, NYU Langone Health , New York, NY, USA.

Background: Allgrove syndrome is a multisystem disorder first described in 1978 and is classically associated with esophageal achalasia, alacrima, and adrenal insufficiency. Allgrove syndrome is caused by homozygous and/or compound heterozygous mutations on Chromosome 12q13, designated as "AAA" (Achalasia, Addisonianism Alacrima). AAA encodes the protein ALADIN (Alacrima, Achalasia, aDrenal Insufficiency Neurologic disorder), a member of the nuclear porin family forming the nuclear pore complex. Read More

Am J Kidney Dis 2019 03 25;73(3):425-428. Epub 2018 Oct 25.

Division of Nephrology, Department of Pediatrics, NYU Langone Health, New York, NY. Electronic address:

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. Read More

Mol Genet Genomic Med 2018 11 31;6(6):1134-1139. Epub 2018 Oct 31.

Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Background: Hereditary spastic paraplegia (HSP) is a group of rare disorders characterized by spastic paraparesis and other symptoms. Often, other diseases can mimic HSP, which may delay diagnosis and treatment.

Methods: Whole exome sequencing was performed in families with clinically suspected HSP without a genetic diagnosis. Read More

J Pak Med Assoc 2018 Aug;68(8):1260-1262

Paediatrics, Bahawal Victoria Hospital.

Allgrove syndrome is a rare autosomal recessive syndrome of unknown prevalence. The first case of Allgrove syndrome was reported in 1978 by Allgrove. It is characterized by triad of achalasia, alacrima and adrenal hypoplasia. Read More

Am J Case Rep 2018 Jun 18;19:705-709. Epub 2018 Jun 18.

Department of Gastroenterology, Yuedong Hospital of the Third Affiliated Hospital of Sun Yat-sen University, Meizhou, Guangdong, China (mainland).

BACKGROUND Adrenal insufficiency is mainly due to insufficient adrenal corticosteroid hormones secretion by the adrenal cortex, which leads to clinical manifestations such as weakness, weight loss, hyperpigmentation, hypotension, and vomiting. However, the clinical manifestations of adrenocortical insufficiency may be atypical: anorexia, ascites, impaired liver function, and alacrima have been reported. Jaundice and anorexia presenting together in the same patient as the main symptoms are rare. Read More