Table 1.
Clinical and laboratory characteristics of patients with RRAGD mutations
| Individuals | F1.1 | F2.1 | F3.1 | F4.1 | F5.1 | F6.1 | F7.1 | F8.1 | F9.1 | Family 9 Median (n=8) |
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | US | France | France | Belgium | Germany | Belgium | Germany | Turkey | Belgium | Belgium |
| Sex | M | F | F | M | F | M | F | M | M | 4F/4M |
| Age at manifestation | 3 yr | 3 yr | 6 mo | 5 yr | 7 mo | 14 yr | 2 yr | 6 yr | 20 yr | 2.5–24 yr |
| Initial findings | ||||||||||
| Dilated cardiomyopathy (age at diagnosis) | Yes (3 yr) | Yes (12 yr) | Yes (6 mo) | No | Yes (7 mo) | Yes (14 yr) | Yes (4 yr) | No | No | No |
| Fractional shortening (%; N>25) | 7 | 8 | 15 | 31 | 15 | — | 18 | — | — | — |
| Ejection fraction (%; N=55–70) | 15 | 31 | — | 61 | 16 | 50 | — | — | — | — |
| Left ventricular end-diastolic diameter (mm)a | 53 (>P99.9)d |
55 (>P99.9)d |
33 (P99.7)d |
34 (P17.1)d |
42 (>P99.9)d |
— | 46 (>P99.9)d |
— | — | — |
| Hypomagnesemia-related symptoms | No | Tetany | Cerebral seizure | Tetany, muscle cramps | No | No | No | Cerebral seizure | Tetany, muscle cramps | 7/8 |
| Nephrocalcinosis | Yes | Yes | Yes | No | Yes | No | Yes | Yes | No | 1/8 |
| Polyuriab | No | No | Yes | No | Yes | No | Yes | Yes | Yes | 2/8 |
| Metabolic alkalosis | No | ? | Yes | Yes | No | No | No | Yes | Yes | 4/8 |
| Initial laboratory findings | ||||||||||
| S-Na (mmol/L; N=138–145) | 135 | — | 137 | 137 | 141 | 136 | 142 | 141 | 140 | 139 |
| S-K (mmol/L; N=3.5–5.0) | 4.7 | 3.2 | 3.5 | 3,4 | 3.5 | 3.5 | 3.9 | 2.7 | 3.5 | 3.3 |
| S-Cl (mmol/L; N=98–106) | 98 | — | 95 | — | 100 | 95 | 105 | 91 | 95 | 98,5 |
| S-Ca (mmol/L; N=2.20–2.70) | 2.05 | 1.78 | 2.20 | 2.2 | 2.11 | 2.37 | 2.50 | 1.8 | 2.41 | 2.36 |
| S-Mg (mmol/L; N=0.60–0.95) | 0.50 | 0.27 | 0.40 | 0.43 | 0.40 | 0.42 | 0.54 | 0.26 | 0.54 | 0.49 |
| S-PO4 (mmol/L; N=1.20–1.80) | 1.56 | — | 1.44 | 1.59 | 1.50 | — | 1.53 | 1.7 | 0.87 | 1.00 |
| S-creatinine (mg/dl) | 0.51 | 0.70 | 0.24 | 0.23 | 0.21 | 0.75 | 0.30 | 0.47 | 0.74 | 0.51 |
| S-HCO3 (mmol/L; N=22–29) | — | — | 24 | 29.3 | — | — | 28.5 | 29.1 | — | — |
| iPTH (pg/ml; N=9–65) | 33 | — | 17 | 29 | 37 | — | 91 | 108 | 21 | 18 |
| FE-Na (%; N<2) | 1.0 | — | 0.34 | 0,4 | 0.8 | — | 0.9 | 0.34 | 0.4 | 0.40 |
| FE-K (%; N=4–16) | 13 | — | 27 | 6,3 | 24 | — | 23 | 14 | 7.5 | 6.2 |
| Ca-Crea ratio (mol/mol; N<0.9) | 0.67 | 1.8 | 1.24c | 0.12 | 1.46c | — | 2.27 | 1.38 | 0.25 | — |
| FE-Mg (%; N< 4) | 47 | 13.2 | 7.0 | 4.3 | 16 | — | 13.2 | 13.8 | 3.7 | — |
| Follow-up findings | ||||||||||
| Age at last follow-up (yr) | 6 | 20 | 14 | 10 | 35 | 5 | 19 | 40 | 2.5–61 | |
| Heart transplant (age) | Yes (3.3 yr) | Yes (25 yr) | Yes (15 yr) | No | No | No | No | No | No | No |
| Fractional shortening (%; N>25) | d.n.a. | d.n.a. | d.n.a. | 33 | 22 | 14 | 28 | 38 | — | — |
| Ejection fraction (%; N=55–70) | d.n.a. | d.n.a. | d.n.a. | 62 | 41 | 45 | 50 | 67 | 78 | 60–78 |
| Left ventricular end-diastolic diameter (mm)a | d.n.a | d.n.a. | d.n.a. | 37 (P1.8)d |
42 (P77.3)d |
49 | 43 (>P99.9)d |
48 | — | — |
| Most recent laboratory findings | ||||||||||
| S-Na (mmol/L; N=135–145) | 138 | — | 140 | 140 | 139 | 140 | 142 | 141 | 140 | 140 |
| S-K (mmol/L; N=3.5–5.0) | 4.6 | — | 3.7 | 3,3 | 3.3 | 4.6 | 3.2 | 3.5 | 3.5 | 3.4 |
| S-Cl (mmol/L; N=98–107) | 104 | 100 | 100 | 103 | 104 | 95 | 97 | 98 | ||
| S-Ca (mmol/L; N=2.20–2.65) | 2.57 | — | 2.34 | 2,41 | 2.50 | 2.42 | 2.40 | 2.27 | 2.3 | 2.4 |
| S-Mg (mmol/L; N=0.7–1.1) | 0.58 | — | 0.43 | 0,55 | 0.50 | 0.62 | 0.66 | 0.53 | 0.46 | 0.48 |
| S-creatinine (mg/dl) | 0.47 | — | 0.64 | 0,52 | 0.60 | 1.18 | 0.40 | 0.69 | 0.67 | 0.57 |
| S-HCO3 (mmol/L; N=22–26) | 23.0 | — | 28.0 | 25.0 | 27.0 | 24.1 | 24.2 | 29.9 | 35.0 | 29.4 |
| iPTH (pg/ml; N=10–65) | 94 | — | 54 | / | 34 | 17.4 | 60 | 41 | 18 | 17 |
| FE-Na (%; N<2) | 1.0 | — | 1.00 | 0.34 | 1.04 | 0.67 | 0.9 | 0.79 | 0.77 | 0.57 |
| FE-K (%; N=4–16) | 15.5 | — | 11.0 | 33.7 | 18.9 | 13.8 | 34 | 18.2 | 12.1 | 10.7 |
| FE-Cl (%) | 2.71 | — | — | — | 1.52 | — | — | — | — | — |
| Ca-Crea ratio (mol/mol; N<0.9) | 0.34 | — | 0.09 | 0.22 | 0.25 | 1.02 | 1.14 | 0.08 | 0.37 | — |
| FE-Mg (%; N<4) | 26.0 | — | 6.3 | 17.5 | 12.8 | 3.3 | 9.4 | 14.6 | 5.9 | 5.2 |
| Therapy | ||||||||||
| Magnesium supplementation | Yes | ? | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 6/8 |
| Potassium supplementation | No | ? | Yes | Yes | Yes | No | Yes | Yes | No | 3/8 |
| Heart failure medication | Yes | ? | Yes | No | Yes | Yes | Yes | No | No | 0/8 |
| Genetic findings (RRAGD mutations) | ||||||||||
| Nucleotide level | c.227C>T | c.356C>G | c.662T>A | c.227C>T | c.356C>G | c.227C>T | c.356C>T | c.227C>G | c.289A>C | c.289A>C |
| Protein level | p.Ser76Leu | p.Pro119Arg | p.Ile221Lys | p.Ser76Leu | p.Pro119Arg | p.Ser76Leu | p.Pro119Leu | p.Ser76Trp | p.Thr97Pro | p.Thr97Pro |
| Inheritance | De novo | De novo | De novo | Dominant? | De novo | De novo | Maternal mosaicism | De novo | Dominant | Dominant |
US, United States; M, male; F, female; ?, unknown; S, serum; Na, sodium; K, potassium; Cl, chloride; Mg, magnesium; PO4, phosphate; HCO3, bicarbonate; iPTH, intact parathyroid hormone; FE, fractional excretion; Ca-crea ratio, calcium-creatinine ratio; d.n.a., does not apply.
a
Calculations according to Pettersen et al.57
b
>2 L/m2 body surface area per day.
c
Molar Ca-crea ratio N <2.2 for infants.
d
P = percentile of reference weight and height adjusted reference values.