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Alacrima, achalasia, and intellectual disability syndrome(AAMR)

MedGen UID:
1640947
Concept ID:
C4706563
Disease or Syndrome
Synonyms: AAMR; ALACRIMA, ACHALASIA, AND IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; Alacrima, achalasia, and mental retardation syndrome
SNOMED CT: Intellectual disability, alacrima, achalasia syndrome (763741001)
 
Gene (location): GMPPA (2q35)
 
Monarch Initiative: MONDO:0014219
OMIM®: 615510

Definition

Alacrima, achalasia, and impaired intellectual development syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing deficits. The disorder shows similarity to the triple A syndrome (231550), but patients with AAMR do not have adrenal insufficiency (summary by Koehler et al., 2013). See also 300858 for a phenotypically similar disorder that shows X-linked inheritance. [from OMIM]

Clinical features

From HPO
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Achalasia
MedGen UID:
5023
Concept ID:
C0014848
Disease or Syndrome
A disorder of esophageal motility characterized by the inability of the lower esophageal sphincter to relax during swallowing and by inadequate or lacking peristalsis in the lower half of the body of the esophagus.
Esophageal stenosis
MedGen UID:
5026
Concept ID:
C0014866
Disease or Syndrome
An abnormal narrowing of the lumen of the esophagus.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Orthostatic hypotension
MedGen UID:
43803
Concept ID:
C0020651
Disease or Syndrome
A form of hypotension characterized by a sudden fall in blood pressure that occurs when a person assumes a standing position.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Somatic sensory dysfunction
MedGen UID:
1790456
Concept ID:
C5551413
Finding
An abnormality of the primary sensation that is mediated by peripheral nerves (pain, temperature, touch, vibration, joint position). The word hypoesthesia (or hypesthesia) refers to a reduction in cutaneous sensation to a specific type of testing.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Neonatal respiratory distress
MedGen UID:
924182
Concept ID:
C4281993
Finding
Respiratory difficulty as newborn.
Hypernasal speech
MedGen UID:
99115
Concept ID:
C0454555
Finding
A type of speech characterized by the presence of an abnormally increased nasal airflow during speech associated with structural abnormality of the nasal passages.
Prominent nose
MedGen UID:
98423
Concept ID:
C0426415
Finding
Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Anatomical Abnormality
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.
High anterior hairline
MedGen UID:
477667
Concept ID:
C3276036
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD above the mean. Alternatively, an apparently increased distance between the hairline and the glabella.
Hypohidrosis
MedGen UID:
43796
Concept ID:
C0020620
Disease or Syndrome
Abnormally diminished capacity to sweat.
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.
Anisocoria
MedGen UID:
1944
Concept ID:
C0003079
Finding
Anisocoria, or unequal pupil size, may represent a benign physiologic variant or a manifestation of disease.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Alacrima
MedGen UID:
87488
Concept ID:
C0344505
Disease or Syndrome
Absence of tear secretion.
Exodeviation
MedGen UID:
1637525
Concept ID:
C4551670
Disease or Syndrome
A manifest or latent ocular deviation in which one or both eyes tends to deviate temporally.

Recent clinical studies

Etiology

Diaz J, Kane TD, Leon E
Am J Med Genet A 2020 Mar;182(3):425-430. Epub 2020 Jan 3 doi: 10.1002/ajmg.a.61476. PMID: 31898852

Diagnosis

Smits DJ, Dekker J, Douben H, Schot R, Magee H, Bakhtiari S, Koehler K, Huebner A, Schuelke M, Darvish H, Vosoogh S, Tafakhori A, Jameie M, Taghiabadi E, Wilson Y, Shah M, van Slegtenhorst MA, Medici-van den Herik EG, van Ham TJ, Kruer MC, Mancini GMS
HGG Adv 2024 Oct 10;5(4):100327. Epub 2024 Jul 14 doi: 10.1016/j.xhgg.2024.100327. PMID: 39003500Free PMC Article
Geiculescu I, Dranove J, Cosper G, Edmondson AC, Morava-Kozicz E, Carter LB
Am J Med Genet A 2022 Aug;188(8):2438-2442. Epub 2022 Jun 4 doi: 10.1002/ajmg.a.62859. PMID: 35665995Free PMC Article
Marom D, Albin A, Schwartz C, Har-Zahav A, Straussberg R, Bartel F, Birk E, Inbar D, Basel-Vanagaite L
Am J Med Genet A 2011 Aug;155A(8):1959-63. Epub 2011 Jul 8 doi: 10.1002/ajmg.a.34121. PMID: 21744492
Kurca E, Grofik M, Kucera P, Varsik P
Neuro Endocrinol Lett 2005 Oct;26(5):499-502. PMID: 16264411
Zeharia A, Shuper A, Mimouni M, Kornreich L, Rachmel A, Lerman-Sagie T
J Child Neurol 1999 May;14(5):331-4. doi: 10.1177/088307389901400512. PMID: 10342602

Therapy

Kurca E, Grofik M, Kucera P, Varsik P
Neuro Endocrinol Lett 2005 Oct;26(5):499-502. PMID: 16264411

Prognosis

Kimber J, McLean BN, Prevett M, Hammans SR
J Neurol Neurosurg Psychiatry 2003 May;74(5):654-7. doi: 10.1136/jnnp.74.5.654. PMID: 12700313Free PMC Article

Clinical prediction guides

Marom D, Albin A, Schwartz C, Har-Zahav A, Straussberg R, Bartel F, Birk E, Inbar D, Basel-Vanagaite L
Am J Med Genet A 2011 Aug;155A(8):1959-63. Epub 2011 Jul 8 doi: 10.1002/ajmg.a.34121. PMID: 21744492

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