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Am J Med Genet A 2022 Jun 4. Epub 2022 Jun 4.

Department of Pediatrics, Division of Medical Genetics, Levine Children's Hospital, Atrium Health, Charlotte, North Carolina, USA.

Achalasia is rare in the pediatric population and should prompt clinicians to consider genetic disorders associated with this condition. While AAA syndrome (also known as Allgrove or Triple A syndrome) is commonly considered, GMPPA-congenital disorder of glycosylation (CDG) should also be in the differential diagnosis. We report a 9-month-old female born to nonconsanguineous parents with achalasia and alacrima found to have two novel compound heterozygous variants in the GMPPA gene associated with GMPPA-CDG. Read More

PLoS Genet 2022 06 2;18(6):e1010228. Epub 2022 Jun 2.

Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.

NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Read More

Ophthalmic Genet 2022 May 23:1-3. Epub 2022 May 23.

Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, USA.

Purpose: Alacrima is characterized by severely decreased or deficient tear production. It can be associated with systemic findings; most commonly Triple-A Syndrome with alacrima, achalasia, and adrenal dysfunction.

Methods: A case report and review of the literature. Read More

Mol Genet Genomic Med 2022 May 15:e1966. Epub 2022 May 15.

Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.

Background: Achalasia-addisonianism-alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD-repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Read More

Cureus 2022 Mar 26;14(3):e23527. Epub 2022 Mar 26.

Department of Endocrinology, Kali Prasad Chowdhury Medical College and Hospital, Kolkata, IND.

Congenital adrenal hypoplasia or adrenal hypoplasia congenita (AHC) is a rare disorder ascribed to mutations in three genes, namely, the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1/NROB1 gene), steroidogenic factor-1 gene (SF-1/NR5A1 gene), and Achalasia-Addisonianism-Alacrima syndrome gene (AAAS gene). Five cases of AHC of local South Asian origin are described here. Golden Helix VarSeq 2. Read More

Case Rep Otolaryngol 2021 19;2021:1315117. Epub 2021 Nov 19.

Hôpital de l'Enfant-Jésus, Québec (QC) G1J 1Z4 1401, 18 rue, Canada.

Introduction: Triple "A" syndrome (TAS) is a rare autosomal recessive disorder that presents in childhood with achalasia cardia, alacrima, ACTH-resistant adrenal insufficiency, with sensorimotor and autonomic polyneuropathy developing later in the course of the disease. . An adult white male affected by this syndrome underwent an uneventful total thyroidectomy for malignancy and suffered delayed bilateral recurrent laryngeal nerve palsy in the early postoperative hours. Read More

Ann Med Surg (Lond) 2021 Dec 10;72:103009. Epub 2021 Nov 10.

Department of Endrocinology Medicine, University Aleppo Hospital, Aleppo, Syria.

Triple A syndrome 3A (Allgrove syndrome) is a rare autosomal recessive multiorgans dysfunction characterized by alacrima, achalasia which is the absence of esophageal muscle peristalsis and lower sphincter failure to relax and adrenal insufficiency. About third of patient additional features like neurological and autonomic manifestations reported (making the syndrome 4A), the spectrum of neurological symptoms varies including gait disturbances, parkinsonism, muscle wakeness, mental retardation, peripheral sensory and motor neuropathy. Here we reported A 18 years old male, who had postnatal recurrent conjunctivitis so alacrima was diagnosed, in the sventh years he developed achalasia signs; dysphagia and regurgitation and laparscopic surgical myotomy and fundoplication were done, when he became 16 he presented to our clinic for poor appetite, weight loss,and failure to thrive. Read More

Child Neurol Open 2021 Jan-Dec;8:2329048X211031059. Epub 2021 Oct 4.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.

Allgrove or "Triple A" syndrome is characterized by alacrima, achalasia, and adrenocorticotropic hormone-resistant adrenal insufficiency, as well as central and peripheral nervous system involvement. Patients demonstrate heterogeneity with regard to their age of symptom onset, disease severity, and nature of clinical symptoms. Neurophysiological testing has also shown variability ranging from: motor neuron disease with prominent bulbar involvement, motor-predominant neuropathy, or sensorimotor polyneuropathy with axonal or mixed axonal and demyelinating features. Read More

J Biochem 2022 Feb;171(2):177-186

Grace Science, LLC - Menlo Park, CA, USA 94025.

Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as surrogate markers for therapy response. N-glycanase 1 (NGLY1) deficiency is an ultra-rare autosomal recessive disorder characterized by developmental delay, peripheral neuropathy, elevated liver transaminases, hyperkinetic movement disorder and (hypo)-alacrima. We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls. Read More

Clin Pediatr Endocrinol 2021 1;30(4):195-200. Epub 2021 Oct 1.

Department of Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan.

Multiple endocrine neoplasia type 2B (MEN2B) is an extremely rare disease, most often caused by a p.Met918Thr mutation. Medullary thyroid carcinoma of MEN2B has a good prognosis if diagnosed by one year of age. Read More

Orbit 2022 Apr 5;41(2):162-169. Epub 2021 Sep 5.

Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.

The congenital absence of tear production or alacrima is a distinctively unusual clinical sign that harbors a wide variety of etiologies. While alacrima can be only isolated to the lacrimal system, it is more often associated with progressive multisystem involvement from underlying genetic disorders. Recognizing the subtle ocular signs in these diseases will promote a timely diagnosis and management before potential life-threatening consequences occur. Read More

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2022 Mar 24;166(1):105-111. Epub 2021 Aug 24.

Department of Paediatrics, Charles University in Prague, Faculty of Medicine in Pilsen, Czech Republic.

Background: We describe early and typical nonendocrine symptoms of Multiple Endocrine Neoplasia type 2B (MEN2B) presented in our patients with de novo M918T mutation in the RET proto-oncogene in early childhood, however, the diagnosis of MEN2B and medullary thyroid carcinoma (MTC) was confirmed late, in the second decade of life. In this paper, we emphasize the possibility of growth retardation, growth hormone (GH) deficiency and ovarian teratoma as a new symptom of MEN2B.

Case Reports: Advanced MTC with palpable mass on the neck and nonendocrine symptoms such as marfanoid habitus, thickened lips, mucosal neuromas led to the diagnosis in case 1 at the age of 13 years and GH deficiency and nonendocrine symptoms in case 2 at the age of 11 years. Read More

Rev Gastroenterol Mex (Engl Ed) 2021 Oct-Dec;86(4):441-443. Epub 2021 Aug 18.

Departamento de Gastroenterología, Hepatología y Nutrición Pediátrica, Unidad de Procedimientos, Yale University School of Medicine, New Haven, CT, United States.

Mol Brain 2021 06 13;14(1):91. Epub 2021 Jun 13.

Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1-/-, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Read More

J Clin Invest 2021 05;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