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. 2021 Jun 7;12:668640. doi: 10.3389/fneur.2021.668640

Table 1.

Overview of demographic, genomic, biochemical, and clinical data of nine patients with NANS-CDG.

Demographics Patient 1 Patient 2 Patient 3 Patient 4
Ancestry Canadian/European (the Netherlands) European (the Netherlands) European (the Netherlands) European (Hungary)
Gender Male Male Male Female
Age at evaluation 8 years 1–3 months 2 years 10 months
Age molecular diagnosis 3 years Prenatal (31 weeks 0 days) 6 months 10 months
Genotypic spectrum
NANS DNA variants c.709C>T; c.562T>C c.709C>T; c.562T>C c.709C>T; c.562T>C c.709C>T; c.440C>A
Genomic DNA positiona g.100843203; g.100840588 g.100843203; g.100840588 g.100843203; g.100840588 g.100843203; g.100839291
Variant type (protein effect) Missense; missense Missense; missense Missense; missense Missense; missense
Amino acid change p.(Arg237Cys); p.(Tyr188His) p.(Arg237Cys); p.(Tyr188His) p.(Arg237Cys); p.(Tyr188His) p.(Arg237Cys); p.(Ala147Asp)
gnomAD frequencyb 0.00001314; 0.00003291 0.00001314; 0.00003291 0.00001314; 0.00003291 0.00001314; 0.00001973
PolyPhen scoreb Probably damaging; probably damaging Probably damaging; probably damaging Probably damaging; probably damaging Probably damaging; probably damaging
SIFT scoreb Deleterious; deleterious Deleterious; deleterious Deleterious; deleterious Deleterious; deleterious
ClinVarb Pathogenic; pathogenic Pathogenic; pathogenic Pathogenic; pathogenic Pathogenic; unknown
CADD scorec 32; 27.2 32; 27.2 32; 27.2 32; 29.9
Biochemical spectrum
ManNAc excretion in urine (μmol/mmol creatinine, ref 0 μmol/mmol creatinine) 295e 330; 297f 405; 520g 530h
ManNAc increase in plasma (fold change in NGMS vs. controls) 11× 25× 10× Plasma not available
Phenotypic spectrum
Birth parameters
Gestational age (weeks + days) 41+3 40+5 39+3 37+0
Birth weight (g) 2,865 (P4) 3,000 (P7) 3,228 (P23) 2,190 (P < 2.5)
Birth height (cm) 47 (P5) NR 46 (P2) 40 (<P2)
Head circumference (cm) NR 32 (<P2.5) 35 (P82) 29 (<P2.5)
Apgar scores (after 1, 5, 10 min) NR 6, 8, 9 3, 8, 10 9, 10, 10
Neonatal jaundice Y (phototherapy) Y Y (phototherapy) Y
Respiratory distress N N Y N
Complications at birth Skeletal dysplasia Hypotonia; skeletal dysplasia; petechiae; polycythemia; metabolic compensated respiratory acidosis; thrombocytopenia Axial hypotonia; skeletal dysplasia; hyperlaxity; dysfunctional sucking Skeletal dysplasia; hydrocephalus
Interventions at birth N Tube feeding Vit. K supp.; short-term oxygen support; tube feeding N
Psychomotor development and cognition
Intellectual disability +++(home schooled, nurse participates in care) NA NA NA
IQ range NR NA NA NA
Adaptive functioning Delayed NA Delayed Delayed
Global developmental delay ++++ + +++ ++
Gross motor skills Delayed, no ambulation NA Delayed (according to Bayley scale), no ambulation Delayed
Fine motor skills Delayed (unspecified) NA Delayed (according to Bayley Scale) NR
Language development No speech NA Delayed NA
Neurologic symptoms
Seizure history Y N N Y
Abnormalities of muscle tone Generalized hypotonia Axial hypotonia Axial hypotonia; limb hypertonia Axial, limb hypotonia
Muscle strength Inadequate Normal Inadequate around hips Inadequate
Reflexes NR NR Absence of menace reflex NR
Ataxia NR NR N N
Cranial nerves Intact NR NR NR
Other neurological abnormalities Hydrocephalus N Dystonia; spasticity; tremor West syndrome
Neuroimaging (MRI) At age 4 months−3.5 years: Ventriculomegaly; Abnormality in periventricular white matter; Cerebral atrophy; Persistent vacuum vergae; Abnormal basal nuclei; Hypoplasia of the corpus callosum and splenium, aplasia rostrum; Asymmetry of cerebellum Prenatal: Hypoplastic cerebellum; Periventricular pseudocysts; Polymicrogyria Postnatal (2 days): Ventriculomegly; Cerebral atrophy; Widened cisternae and/or sulci; Hypoplastic brainstem; Hypoplastic cerebellum; Periventricular pseudocysts; Cavum septum pellucidum; Cerebellar hemorrhage; Abnormal corpus callosum with hypoplastic splenium Prenatal: Suspected hypoplastic cerebellum; Small cavum septum pellucidum; Mild ventriculomegaly; Suspected syntelencephaly Postnatal (4 days): Small but anatomically normal cerebellum; Moderate ventriculomegly; Limited volume of corpus callosum and periventricular white matter; Small optic chiasm; Absence of septum pellucidum; Suggestion of cortical malformation of the left temporoparietal region At 2 years: Progressive white > gray matter atrophy; Severe ventriculomegaly; Aqueduct stenosis At 8 months: Enlarged lateral ventricles and third ventricle; Cerebral atrophy; Absent splenium of the corpus callosum; Aqueduct stenosis
Somatic growth
Age 8.5 years 3 months Age 26 months Age 10 months
Length (cm) 91 (<P0.01) 56 (P0.4) 76.2 (P0.01) 57 (<P0.01)
Weight (kg) 19.8 (P0.5) 5.435 (P8) 9.426 (P0.01) 5.3 (<P0.01)
Head circumference (cm) NR 41 (P85) 48.3 (P31) 39 (<P0.01)
Short stature Y Y Y Y
Bones
Skulld Frontal bossing NR Frontal bossing NR
Spined Flat vertebra; Irregular calcification of the endplates; Scoliosis and lumbar kyphosis NR L2 ventroapical deformity, resulting in kyphosis and scoliosis; Abnormal ossification centers (CT) NR
Pelvisd Sclerosis iliac crest; Flat acetabular roofs; Shallow acetabula; Short femoral neck NR Small iliac wings; Shallow flat acetabula; Small femoral head epiphysis; Short femoral neck; Luxated left hip NR
Limbsd Upper extremities: Metaphyseal widening distal ulna and radius Lower extremities: NR Upper extremities: Metaphyseal widening; Sclerosis; Irregularity Lower extremities: Metaphyseal widening; Sclerosis; Irregularity Upper extremities: Metaphyseal widening; Sclerosis; Irregularity Lower extremities: Metaphyseal widening; Sclerosis; Irregularity Upper extremities: Metaphyseal widening; Sclerosis; Irregularity; Small flat epiphysis distal radius Lower extremities: Metaphyseal widening; Sclerosis; Irregularity; Genu vara
Joint hypermobility NR NR Y N
External features
Facial dysmorphisms Y Y Y Y
Skin anomalies N N N N
Eye
Strabismus; amblyopia; myopia; cone-red dystrophy; visual impairment Strabismus Delayed visual development Strabismus
Heart
Dilated aortic root and abdominal aorta Normal Normal Normal
Auditory
Conductive hearing loss Normal Normal Abnormal BERA test 1 side
Gastrointestinal and nutrition
Constipation +++ N +++ Y
Abdominal distention ++ + +++ Y
Other pathology GastroesophageaI reflux; G-J tube in situ; partial bowel obstruction Anus perforatus N N
Urinary tract
Urinary tract Neurogenic bladder NR Normal Urethral stenosis; hydronephrosis; hydroureter
External genitalia development NR Normal Normal Normal
Onset of puberty NA NA NA NA
Immunologic (recurrent infections)
Y N Y Y
Other striking features
Obstructive sleep apnea Positional preference right; Flattened aspect hands Positional preference right; Excessive mucus production Excessive mucus production
Clinical severity
Clinical severity classification Profound Mild-moderate Profound Profound
NPCRS 48 13 40 38
Laboratory findings
Hematology
Anemia N N N Y
Thrombocytopenia Y Y Y Y
Biochemistry
Lactate NR Normal ↑(Recovered) NR
Electrolytes Normal Normal Normal Normal
Kidney function Normal Normal Normal Normal
Liver/biliary function ↓Alkaline phosphatase ↑Alkaline phosphatase ↑Alkaline phosphatase ↑Alkaline phosphatase
Lipids NR ↓LDL ↓LDL Normal
Endocrine Normal NR Normal Normal
Demographics Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
Ancestry European (Germany/Russia) European (Iceland) European (Dutch) European (Denmark) European (Dutch)
Gender Female Female Male Male Female
Age at evaluation 7 years 13 years 16 years 17 years 28 years
Age molecular diagnosis 6 years 10 years 11 years 15 years 25 years
Genotypic spectrum
NANS DNA variants c.1A>G; c.449–10_449–5delGATTACinsATGG c.351G>A; c.922_925dup c.710G>A; c.92del c.88C>T; c.200T>G c.709C>T homozygous
Genomic DNA positiona g.100819091; g.100840465 g.100839202; g.100845179_100845182dup g.100843204; g.100819182 g.100819178; g.100823131 g.100843203
Variant type (protein effect) Start_lost; splice-region_variant; intron_variant Missense; frameshift Missense; frameshift Stop_gain; missense Missense
Amino acid change p.(Met1?); unknown p.(Met.117IIe); p.(Met309Asnfs*11) p.(Arg237His); p.(Gly31Alafs*5) p.(Gln30*); p.(Leu67Trp) p.(Arg237Cys)
gnomAD frequencyb 0.000006595; unknown 0.001302; 0.000007954i 0.000006570; 0.00001314 Unknown; 0.00001314 0.00001314
PolyPhen scoreb Benign; unknown Benign; unknown Possibly damaging; unknown Unknown; benign Probably damaging
SIFT scoreb Deleterious_low_confidence; unknown Tolerated; unknown Deleterious; unknown Unknown; deleterious Deleterious
ClinVarb Unknown; pathogenic Benign; unknown Unknown; unknown Unknown; unknown Pathogenic
CADD score 24; 18.01 24.3; 23.2 29.5; 32 41; 25 32
Biochemical spectrum
ManNAc excretion in urine (μmol/mmol creatinine, ref 0 μmol/mmol creatinine) Urine not available 46j 45k 10l Urine not available
ManNAc increase in plasma (fold change in NGMS vs. controls) Plasma not available Plasma not available 2× 3× 6×
Phenotypic spectrum
Birth parameters
Gestational age (weeks + days) 35+0 Full term 40+5 40+0 41+3
Birth weight (g) 1,550 g (<P2.5) 3,000 (P8) 3,620 (P48) 4,560 (P97) 3,920 (P82)
Birth height (cm) NR 48 (P25) 50 (P50) NR 48 (P25)
Head circumference (cm) NR 36 (P95) NR NR 37 (P98)
Apgar scores (after 1, 5, 10 min) NR NR Unremarkable 4, 5, 6 10, 10, 10
Neonatal jaundice NR N NR N Y
Respiratory distress N N Y N N
Complications at birth N Skeletal dysplasia NR Low blood pressure; hypotonia Skeletal dysplasia; recurrent choking
Interventions at birth Tube feeding; care at the NICU (prematurity) N Short-term oxygen support Intravenous saline NR
Psychomotor development and cognition
Intellectual disability +++(attending special school) +++(attending special school, autism) +(attending special school) +(attending special school) +++(lives in nurse home)
IQ range NR 20–40 (age and test unspecified) 60–75 (according to WISC-III-NL) 56 (age 6, test unspecified) NR
Adaptive functioning Delayed Delayed Delayed Delayed Delayed
Global developmental delay +++ +++ + + ++++
Gross motor skills Unaided ambulation Unaided ambulation, mild mobility problems Unaided ambulation Unaided ambulation Delayed, no ambulation
Fine motor skills NR NR Delayed (unspecified) Delayed (unspecified) Delayed (unspecified)
Language development Delayed No speech Delayed Delayed, dyspraxia No speech
Neurologic
Seizure history N N N N Y
Abnormalities of muscle tone Hypotonia Hypotonia Generalized hypotonia Hypotonia Generalized hypertonia
Muscle strength Mild weakness Mild weakness Normal NR Inadequate
Reflexes NR NR Hyperreflexia NR Low-normal
Ataxia Y (mild) Y (mild) N N Y
Cranial nerves NR NR NR NR NR
Other N N NR N N
Neuroimaging (MRI) At 2 years: Persistent cavum septum pellucidum At 11 years: CT scan: normal At 12 years: Cavum septum pellucidum and vergae NR At 9 months: Ventriculomegaly At 3 years: Cerebral atrophy; widened cisternae and/or sulci; atrophy of the caudate nucleus; At 15 years: Ventriculomegaly; cavum septum pellucidum
Somatic growth
Age 7 years Age 8.5 years Age 16 years Age 13.5 years Age 26 years
Length (cm) 105.6 (<P0.01) 115 cm (<P0.01) 151.3 cm (P0.3) 160.6 (P44) 126 (<P0.01)
Weight (kg) 17.2 (P0.5) 20 kg (P0.3) 47.3 kg (P5) 70 (P95) 30 (<P0.01)
Head circumference (cm) 50 (P10) NR 55 cm (P80) NR 58 (>P95)
Short stature Y Y Y N Y
Bones
Skulld NR NR NR NR NR
Spined Vertebral plates sclerosis from dorsal to ventral over time; Increased lumbar lordosis Vertebral plates abnormal sclerosis from dorsal to ventral over time, resulting in wavy double contour plates Double contour of the vertebral plates with less calcification anterior NR Scoliosis
Pelvisd NR Small iliac wings; Small femoral heads and neck Small iliac wings, dysplastic acetabula; Small femoral heads and neck NR Small femoral head and neck
Limbsd Upper extremities: Metaphyseal widening; Sclerosis; Irregularity distal ulna and radius Lower extremities: NR Upper extremities: Metaphyseal widening; Sclerosis; Irregularity distal ulna and radius Lower extremities: Metaphyseal irregular striated sclerosis; Dysplastic knee joints; Fibular overgrowth cf. tibia Upper extremities: Subtle metaphyseal widening and sclerosing Lower extremities: Subtle metaphyseal widening and sclerosing; Striated sclerosing at knee metaphysis with small irregular epiphysis NR Upper extremities: Small epiphyses Lower extremities: Small epiphyses
Joint hypermobility N N Y NR Y
External features
Facial dysmorphisms Y Y Y Y Y
Skin anomalies NR NR Eczema NR N
Eye
Mild strabismus; hyperopia Strabismus; nystagmus Normal Normal Normal
Heart
Normal Normal Normal NR Normal
Auditory
Normal Normal Normal Normal Normal
Gastrointestinal and nutrition
Constipation N N N N +++
Abdominal distention N N NR N ++
Other pathology N N Swallowing difficulty during infancy N NR
Urinary tract
Urinary tract Normal Normal NR NR Bladder emptying disorder
External genitalia development NR NR NR NR Normal
Onset of puberty NA No Age-adequate Age-adequate NR
Immunologic (recurrent infections)
N NR Y N Y
Other features
N NR N Overweight Excessive mucus production
Clinical severity
Clinical severity classification Severe Mild Mild Mild Severe-profound
NPCRS 21 19 13 8 36
Laboratory findings
Hematology
Anemia N N N NR Ym
Thrombocytopenia N N N NR Yn
Biochemistry
Lactate Normal NR Normal NR ↑(Recovered)
Electrolytes Normal Normal Normal NR Normal
Kidney function Normal Normal Normal NR Normal
Liver/biliary function Normal Normal Normal NR Normal
Lipids Normal Normal ↓LDL; ↓Triglycerides NR ↓LDL
Endocrine Normal Normal Normal NR Normal

+, mild; ++, moderate; +++, severe; ++++, profound; ↑, elevated; ↓, decreased; Y, yes; N, no; NR, not reported; NA, not applicable; NGMS, next-generation metabolic screening; NPCRS, Nijmegen Pediatric CDG Rating Scale.

a

GRCh37.

b

GnomAD v3.1, accessed December 2020, scores determined December 2020.

c

CADD score calculated with GRCh37.

d

Reported on X-ray.

e

Urine sample at age 3 years.

f

Urine samples at age 2 months and 5 months.

g

Urine sample at age 6 months and 24 months.

h

Urine sample at age 10 months.

i

GnomAD v2.1.1.

j

Urine sample at age 10 years.

k

Urine sample at age 12 years.

l

Urine sample at age 17 years.

m

Due to special diet.

n

Measured at age of 23 months, normal platelet count at age 26 and 28 years.