Neurogenetics: Name That Syndrome Flashcards
Slowly progressive weakness and atrophy of distal muscles in the feet and/or hands Onset in the 1st-3rd decades Hearing loss Pes cavus deformity Hip dysplasia
Charcot-Marie Tooth (hereditary motor and sensory neuropathy) -many subtypes classified by inheritance and primary abnormality (abnormal myelin, axonopathy, or both) -usually AD or AR but CMTX is X-linked
Progressive symmetric muscle weakness, proximal>distal Calf hypertrophy Onset before 5 years Cardiomyopathy
Duchenne and Becker Muscular Dystrophy X-linked recessive, mutations in DMD -> decreased or absent dystrophin production or abnormal dystrophin produced CK 10x normal in DMD, CK 5x normal in BMD
Name the disorder and mechanism:
Progressive limb and gait ataxia, absent DTRs in LE Onset before 25 yrs glucose intolerance/diabetes Hypertrophic Cardiomyopathy Scoliosis, optic nerve atrophy
Fredereich’s ataxia Autosomal recessive, triplet repeat disorder (GAA expansion in intron 1) -> loss of transcription of FRDA gene and decreased frataxin 66-1700 repeats disease causing.
Name the disorder and gene.
Recurrent focal pressure palsies Mild polyneuropathy Absent ankle reflexes, reduced DTRs, Pes cavus foot deformity Adult onset
Hereditary neuropathy with liability to pressure palsies PMP22 (deletion in 80%, mutation in 20%) Autosomal dominant
Name the disorder and gene. Multi-systemic disorder of: - skeletal and smooth muscle (myotonia, distal muscle weakness and atrophy) -Eye (early cataracts) -Heart (arrhythmias) -Impaired glucose tolerance Anticipation with successive generations
Myotonic dystrophy Autosomal dominant triplet repeat disease (CTG repeat expansion in 3’ UTR) in DMPK Thought to cause disease through RNA gain of function mechanism: the transcribed CUG repeats interfere with alternative splicing of multiple genes including a chloride channel disease with >50 repeats
Name the disorder and pattern of inheritance. Newborn male infant with macrosomia (BW > 5 kg), coarse facies, post-axial polydactyly.
=Simpson-Golabi-Behmel syndrome -X-linked recessive disorder due to mutations in GPC3 -prenatal onset of overgrowth -macrocephaly often present at birth -cardiac conduction defects are common
Name the disorder and pattern of inheritance. relative macrocephaly, broad forehead, delayed closure of cranial sutures/fontalelle, clavicle defects, dental anomalies.
=cleidocranial dysplasia -autosomal dominant disorder due to defects in RUNX2 -wormian bones and delayed mineralization of pubic bone can be seen -short stature -narrow pelvis may necessitate c=section for pregnant women
Name the disorder and gene. Onset in infancy with muscle weakness, tongue fasciculations, absent DTRs.
Spinal muscular atrophy 95-98% have deletions of exon 7 of SMN1, 2-5% have a SNV # of copies of SMN 2 modifies the severity of the disease (more copies of SMN2, more mild phenotype and later onset of disease)
Which molecular type of Tuberous Sclerosis is more likely to be associated with renal cyts: TSC1 or TSC2
=TSC2 -occurs if contiguous gene deletion with PKD1
What is meant by SMA due to a gene conversion event
SMN1 and SMN2 genes differ in a key amino acid at the beginning of exon 7. In SMN1 it is a T (or SMN1=SMNT), in SMN2 it is a C (or SMN2=SMNC). The presence of SMNC causes exclusion of exon 7 of SMN during RNA splicing and leads to an unstable mRNA that creates a non-functional protein. While most SMA is due to a SMN1 deletion, a SNV at that key residue in exon 7 will convert SMN1 to the SMN2 form and result in a deficiency of SMN1 functional protein
Most cases of SMA or caused by a SMN1 deletion or a point mutation?
=deletion of SMN1
Syndrome
Features
NF1 / Von Recklinghausen Disease
Gene: NF1
Location: 17q11.2
Inheritance: Autosomal Dominant
MC Features:
- cafe au lait patches (more than six greater than 1.5 cms in diameter)
- peripheral neurofibromata
- inguinal freckling
- lisch nodules
- meningiomas + ON gliomas
- ID/ASD/LD
- scoliosis & spinal NFs
Minor Features:
- macrocephaly, short stature, hypertelorism, and thorax abnormalities (pectus excavatum and pectus carinatum) were significantly more common
- cardiac malformations are more common in patients with the NF1 syndrome with a prevalence of about 2.3%. Sudden death might occur due to a coronary artery vasculopathy (Kanter et al., 2006).
- High-grade CNS tumors occur occasionally
Complications: can include plexiform neurofibroma of the eyelid, macrocephaly, short stature, scoliosis, pseudarthrosis of the tibia, hypertension due to renal artery stenosis, phaeochromocytoma, neurofibrosarcomas, meningiomas, and acoustic neuromas.
Dyndrome
Gene
Features
Fragile X Syndrome
Synonym: X-linked Mental Retardation And Macroorchidism
Gene: FMR1
Location: Xq27.3
Inheritance: XLD
Incidence: 1 in approximately 4,000 live-born males
Features
ID/ASD/ADHD/LD
Macroorchidism
Joint laxity
Mandibular prognathia
Large forehead
Macrocephaly (>90th % ile)
Macrotia
Long face
Less Common:
Periventricular heterotopia
Scoliosis
Syndrome
Gene
Inheritance
Neuro Features:
22q11.2 deletion syndrome
Velocardiofacial Syndrome
Gene -TBX1
Location - 22q11.21
Inheritance Mode - Autosomal Dominant
Neuro:
- Hypocalcemic seizures
- Reports of brain malformation (PMG)
- ID
Photos:
- broad, tubular nose
- microagnathia
- microstomia
Syndrome
Features:
22q11.2 deletion
Features:
Specific learning disability
Recurrent infections
Microcephaly
Abnormality of the ear
Bulbous nose
Unilateral primary pulmonary dysgenesis
Nasal speech
Narrow palpebral fissure
Open mouth
Blepharophimosis
Retrognathia
Underdeveloped nasal alae
Hypoparathyroidism/ Hypocalcemia
Congenital Heart Defects
Muscular hypotonia
Impaired T cell function
Short stature
Syndrome
Gene(s)
Features:
TSC1
Gene: TSC1, TSC2
Location: 9q34; 16p13
Inheritance: Autosomal Dominant
Prevalence: 1 in 30-50,000, however recent studies suggest that this might be as high as 1 in 6,000
Features:
Hypomelanotic macules & Adenoma sebaceum (90%)
Shagreen Patches (30%)
ASD/ID & ADHD/LD
Seizures / IS
Achromatic retinal patches
Subungual fibromas (up to 50%)
Renal (60%): angiomyolipoma / cyst / RCC
Astrocytoma / Ependymoma
Cardiac rhabdomyoma
Subependymal nodules (90%)
SEGAs (5%)
Cortical tubers (>50%)
Less Common or Minor:
Hypothyroidism
Premature chromatid separation
Precocious puberty
Dental enamel pits (70%)
Hemimegalencephaly
Pulmonary lymphangiomyomatosis
Syndrome
Gene
Mechanism
AngelmanSyndrome
(Happy Puppet Syndrome, Formerly)
Gene: UBE3A
Location: 15q11.2; 17q21.31?
Causes:
- Microdeletion (maternal)
- UPD (Paternal)
- Imprinting
Features:
GDD / ID
Epilepsy
Clumsiness, ataxic, broad-based, hunched gait
Protruding tongue & drooling & feeding difficulties
Paroxysmal bursts of contagious laughter
Fair Hair & Skin
Generalized hypotonia
Absent speech
Mandibular prognathia
Hypoplasia of the maxilla
Wide mouth / smile
Deeply set eye
Widely spaced teeth
Microcephaly
EEG abnormality (runs of rhythmic delta)
Limb tremor
Abnormal WM on MRI
Syndrome
Location
Mechanisms
Prader-Willi Syndrome; PWS
Gene - SNRPN,SNORD1,MAGEL3
Location - 15q11.2
Mechanisms
- Microdeletion(paternal)
- UDP (maternal)
- Imprinting
Features:
Severe hypotonia is usually present at birth, and feeding difficulties and failure to thrive may predominate in the first year of life. In the second year over-eating may begin, with subsequent obesity. Short stature, mental retardation, hypogonadism and small hands and feet complete the clinical picture.
Syndrome
Hit: Hand-clasping stereotypy
Smith-Magenis Syndrome; SMS
Chromosome 17p11.2 Deletion Syndrome
Gene: RAI1,PMP22
Location: 17p11.2, 17p12
Inheritance: AD Microdeletion
This is a microdeletion syndrome involving chromosome 17p11.2. Greenberg et al., (1991) estimates the incidence to be 1 in 25000. Struthers et al., (2002) screened 1205 patients with mental retardation/developmental delay and found two patients with a 17p11.2 microdeletion. They estimated the prevalence of Smith Megenis syndrome in the population to between 1 in 40,000 and 1 in 60,000. The features are variable, but it is probably the behaviour pattern which might suggest the diagnosis (Smith et al., 1998). Self-destructive behaviour with exotic and unpronounceable names characterises the behaviour profile, such as onychotillomania (they pull out their nails) and polyebolokoilamania (the insertion of foreign bodies into their orifices). Some children bang their heads and bite their wrists with disturbing ferocity.
Photo:
Typical infant phenotype with ‘tented’ upper lip and depressed nasal bridge at birth (a), at age 4 months (b), and with hand-clasping behavior at age 1 year (c) is shown.
Syndrome
Next diagnostic/management step?
Klippel-Feil Syndrome
Gene: PAX1, GDF6, MEOX1
Location: 8q22; 8q23; 20p11, 17q21
Inheritance Mode: Uncertain
The main diagnostic features are a short neck, a low posterior hair line and radiological evidence of fusion of the cervical vertebrae. In its simplest form this would consist of fusion of the bodies of two adjacent vertebrae, but there might be massive fusion and block vertebrae. The defect might also affect the upper thoracic spine resulting in a scoliosis. Additional features might include webbing of the neck, torticollis, and facial asymmetry
* Get an XR spine if concerned
Photo: Note absent neck due to fusion of the bodies of the cervical vertebrae
Syndrome
Most common gene
Noonan Syndrome
Genes: PTPN11
The features of classic Noonan syndrome include short stature, congenital heart defects, and facial dysmorphism (broad forehead, hypertelorism, downslanting palpebral fissures, high-arched palate, and low-set, posteriorly rotated ears). Noonan syndrome 1, the most common subtype of Noonan syndrome, is caused by heterozygous mutations in the PTPN11 gene. Noonan syndrome 1 is more often associated with pulmonary stenosis, short stature, bruising, and thorax deformities.
Additional Features:
- Short stature
- Cryptorchidism
- Webbed neck
- Low-set, posteriorly rotated ears
- Generalized hypotonia
- Asymmetry of the thorax
- Hypertelorism
- Long eyebrows
- Downslanted palpebral fissures
- Frontal bossing
- Macrocephaly
- High anterior hairline
- Hyperkeratosis pilaris
- Mitral stenosis
- Depressed nasal bridge
- Kyphoscoliosis
- CHD
- Ptosis
- Abnormality of the sternum
- Cognitive impairment
Syndrome
MSK abnormalities?
Joubert Syndrome
(occ: cerebellooculorenal syn)
Genes: ~20, most AR
Features:
- Absence or underdevelopment of the cerebellar vermis
- Molar tooth sign
- Hyperapnea or apnea
- Hypotonia
- Ataxia and nystagmus
- ID & GDD
- Physical deformities may be present, such as extra fingers and toes (polydactyly), cleft lip or palate, and tongue abnormalities.
Syndrome
Hint: 5th digit syndrome
Coffin-Siris Syndrome (CSS)
Gene: SMARCB1,SMARCE1,ARID1A,ARID1B,SMARCA4,ARID2,SOX11,DPF2
Inheitance: Most AD
DISEASE OVERVIEW: Coffin-Siris Syndrome (CSS) shows autosomal dominant inheritance and is characterized by intellectual disability, feeding difficulties, distinct facial features, hypertrichosis and aplasia or hypoplasia of the distal phalanx of the fifth and/or additional fingers and nails. In most patients, the syndrome is caused by a mutation in genes (ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2) encoding components of the BAF (mSWI/SNF) complex, which regulates gene expression through chromatin remodeling.
Dysmorphic features: Features characteristic for CSS patients are coarse facial features, sparse scalp hair, low anterior hairline, thick eyebrows, flat nasal bridge, thick alae nasi, large mouth and thick lower lip vermillion.
Syndrome
Hint: Hallmark –> Teeth
KBG Syndrome; KBGS
Gene: ANKRD11
Location: 16q24.3
Inheritance: AD, Microdeletion
Overiview: A syndrome that includes intellectual disability, facial dysmorphism and broad teeth. Macrodontia of the upper central incisors is a distinctive feature in some patients. KBG syndrome is caused by mutations in the ANKRD11 gene and microdeletions in 16q24.3. Intellectual disability is variable. Some achieve an IQ of approximately 60
Features:
- Intellectual disability/ GDD
- Thick eyebrow
- Broad central incisors
- Low posterior hairline
- Macrotia
- Clinodactyly
- Underdeveloped nasal alae
Syndrome
Cornelia De Lange Syndrome
Genes: 5-6; NIPBL
Cornelia de Lange syndrome is characterized by distinctive facial features (synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, microcephaly), short stature, hirsutism, and upper limb reduction defects. Cornelia de Lange syndrome 1 is the most common subtype of Cornelia de Lange syndrome, featuring a variable presentation that can range from mild to severe. Cornelia de Lange syndrome 1 is caused by heterozygous mutations in the NIPBL gene on chromosome 5p13.2.
Syndrome:
Hint: ‘pseudohydrocephalus’
Silver-Russell Syndrome; SRS
Gene: ICR2,ICR1,CDKN1C
Location: 7p11.2
Inheritance: AD, AR, Disomy
Overview: A characteristic facial appearance, prenatal growth retardation and asymmetry of the limbs are the main features of this condition. The head circumference is relatively normal, which gives the impression of ‘pseudohydrocephalus’. The face is small and triangular with frontal bossing, blue sclerae, thin lips with downturned corners, and micrognathia. Minor abnormalities include increased sweating, clinodactyly of the 5th fingers and cafe au lait patches. Intelligence has been thought to be normal, however Lai et al., (1994) studied 25 cases in detail and found that 32% had an IQ below 70 and 40% were reading at least 24 months below their chronological age. The average IQ was 86.
Syndrome
Kabuki Syndrome
Gene: C20orf133, MLL2, KDM6a, KMT2D, RAP1A, RAP1B
Inheritance: XLR, XLD, AD
Overview: An intellectual disability syndrome with short stature and a characteristic face. Developmental delay is mild to moderate and some cases have austistic features. The main diagnostic feature, which is reminiscent of the make-up worn by actors in Kabuki theatre, is the presence of an everted lateral 1/3 of the lower lid and long palpebral fissures. Affected individuals have a broad nasal tip, prominent ear lobes and a cleft or high-arched palate. The 5th finger is short and there is persistence of the fetal finger pads. There are mild radiological changes in the vertebrae.
Syndrome
Gene
Sturge-Weber Syndrome; SWS
Encephalotrigeminal angiomatosis
Meningofacial angiomatosis
Gene: GNAQ
Inheitance: sporadic
Features:
- Cerebral cortical atrophy
- Arachnoid hemangiomatosis
- Buphthalmos
- Macrocephaly
- Intellectual disability
- Facial hemangioma
- Seizure
- Choroidal hemangioma
